Microneedle injection apparatus comprising an inverted actuator

ABSTRACT

A microneedle injection apparatus ( 100 ) comprising an inverted actuator. The apparatus can include a housing ( 102 ) having a base and a cavity, and a microneedle array holder ( 106 ) configured to hold a microneedle array ( 107 ) within the cavity of the housing. The microneedle array holder can be movable between a retracted position, and an extended position. The apparatus can further include an actuator ( 104 ) movable with respect to the housing and the microneedle array holder between a first position and a second position to cause the microneedle array holder to move from the retracted position to the extended position. At least a portion of the actuator can be located on a skin-facing side of the apparatus (e.g., adjacent the base of the housing) and can be configured to be moved from the first position to the second position in response to the apparatus being pressed toward the skin surface.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a national stage filing under 35 U.S.C. §371 of PCT ApplicationNo. PCT/US2014/039140, filed May 22, 2014, which claims priority to U.S.Provisional Application No. 61/829,632, filed May 31, 2013, thedisclosure of which is incorporated herein by reference in its entirety.

FIELD

The present disclosure generally relates to microneedle injectiondevices for applying microneedles to skin and/or delivering an activeagent to skin.

BACKGROUND

Active agents (or drugs) are conventionally administered either orallyor by injection. Unfortunately, many agents can be ineffective or haveradically reduced efficacy when orally administered since they eitherare not absorbed or are adversely affected before entering thebloodstream and thus do not possess the desired activity. Further,orally administered agents may not take effect as quickly as injectedagents. On the other hand, the direct injection of the agent into thebloodstream, while assuring no modification of the agent duringadministration, is a difficult, inconvenient, painful and uncomfortableprocedure which sometimes results in poor patient compliance.

Transdermal delivery can provide a method of administering active agentsthat would otherwise need to be delivered via hypodermic injection orintravenous infusion. In addition, transdermal delivery, when comparedto oral delivery, avoids the harsh environment of the digestive tract,bypasses gastrointestinal drug metabolism, reduces first-pass effects,and avoids the possible deactivation by digestive and liver enzymes.

In some cases, however, the number of molecules that can be effectivelydelivered using transdermal delivery can be limited by the barrierproperties of skin. The main barrier to the transport of moleculesthrough the skin is the stratum corneum (the outermost layer of theskin).

A number of different skin treatment methods have been proposed in orderto increase the permeability or porosity of the outermost skin layers,such as the stratum corneum, thus enhancing drug delivery through orinto those layers. The stratum corneum is a complex structure of compactkeratinized cell remnants separated by lipid domains. The stratumcorneum is formed of keratinocytes, which make up the majority ofepidermal cells, that lose their nuclei and become corneocytes. Thesedead cells comprise the stratum corneum, which has a thickness of onlyabout 10-30 microns and protects the body from invasion by exogenoussubstances and the outward migration of endogenous fluids and dissolvedmolecules. Various skin treatment methods include the use ofmicroneedles, laser ablation, RF ablation, heat ablation, sonophoresis,iontophoresis, or a combination thereof.

Microneedle or micro-pin arrays, also sometimes referred to asmicrostructured transdermal systems (MTSs), provide intradermal deliveryof active agents, which otherwise would not penetrate the stratumcorneum. The sharp microneedle tip is designed to be able to penetratethe stratum corneum layer of the skin, but short enough not to puncturenerve endings, thus reducing or eliminating pain upon insertion.However, the penetration of microneedles to precise levels within theskin tissue and with good reproducibility is often a challenging task.Therefore, unlike the application of traditional patch-based deliverysystems, some existing MTSs require the assistance of external energy toensure efficient and reproducible penetration of microneedles intobiological tissue at desired depths. This assistance can be achieved byutilizing an apparatus device, which can either be used afterpositioning the microneedle array on the skin surface, or the apparatusdevice can be integrated with an array of microneedles and, uponactivation, can deliver the microneedle array into the skin. Themicroneedles help to create microchannels in the skin, which in someembodiments, can facilitate delivering an active ingredient. In someconstructions, active component(s) may be coated on the microneedlearray and delivered directly through the skin when the stratum corneumis punctured by the microneedles. One advantage of MTS systems overother skin treatment methods is a reduced-pain mode of delivery.

SUMMARY

Some embodiments of the present disclosure provide a microneedleinjection apparatus that can include a housing having a base and acavity that extends through the base to define an opening in the base,wherein the base of the housing is configured to be positioned toward askin surface. The apparatus can further include a microneedle arrayholder configured to hold a microneedle array within the cavity of thehousing. The microneedle array holder can be configured to be at leastpartially located in the cavity of the housing and movable with respectto the opening in the base of the housing between (i) a retractedposition in which the microneedle array is recessed within the housingsuch that the microneedle array does not contact the skin surface whenthe base of the housing is positioned on the skin surface and themicroneedle array is coupled to the microneedle array holder, and (ii)an extended position in which at least a portion of the microneedlearray is positioned to contact the skin surface via the opening when thebase of the housing is positioned on the skin surface and themicroneedle array is coupled to the microneedle array holder. Theapparatus can further include an actuator movable with respect to thehousing and the microneedle array holder between a first position and asecond position to cause the microneedle array holder to move from theretracted position to the extended position. At least a portion of theactuator can be located adjacent the base of the housing and can beconfigured to be moved from the first position to the second position inresponse to the apparatus being pressed toward the skin surface.

Other features and aspects of the present disclosure will becomeapparent by consideration of the detailed description and accompanyingdrawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a front assembled top perspective view of a microneedleinjection apparatus according to one embodiment of the presentdisclosure, the apparatus including a cover, and injection assembly, andan infusion assembly.

FIG. 2 is a side view of the apparatus of FIG. 1.

FIG. 3 is a side cross-sectional view of the apparatus of FIGS. 1 and 2.

FIG. 4 is a front, top, partially exploded perspective view of theapparatus of FIGS. 1-3.

FIG. 5 is a front, bottom, partially exploded perspective view of theapparatus of FIGS. 1-4.

FIG. 6 is a front, top, exploded perspective view of the apparatus ofFIGS. 1-5.

FIG. 7 is a side cross-sectional view of the apparatus of FIGS. 1-6, theapparatus shown in a first condition with the cover removed.

FIG. 8 is a close-up, rear, top, partial perspective view of theapparatus of FIGS. 1-7, the apparatus shown in the first condition withthe cover removed.

FIG. 9 is a side cross-sectional view of the apparatus of FIGS. 1-8, theapparatus shown in a second condition.

FIG. 10 is a close-up, rear, top, partial perspective view of theapparatus of FIGS. 1-9, the apparatus shown in the second condition.

FIG. 11 is a side cross-sectional view of the apparatus of FIGS. 1-10,the apparatus shown in a third condition.

FIG. 12 is a close-up, rear, top, partial perspective view of theapparatus of FIGS. 1-11, the apparatus shown in the third condition.

FIG. 13 is a side cross-sectional view of the apparatus of FIGS. 1-12,the apparatus shown in a fourth condition.

FIG. 14 is a close-up front cross-sectional view of the apparatus ofFIGS. 1-13, the apparatus shown in the fourth condition.

FIG. 15 is a close-up front cross-sectional view of the apparatus ofFIGS. 1-14, the apparatus shown in a fifth condition.

FIG. 16 is a side cross-sectional view of the apparatus of FIGS. 1-15,the apparatus shown in the fifth condition.

FIG. 17 is a side cross-sectional view of the apparatus of FIGS. 1-16,the apparatus shown in a sixth condition.

FIG. 18 is a top plan view of the apparatus of FIGS. 1-17, the apparatusshown in the sixth condition.

FIG. 19 is a close-up side cross-sectional view of the apparatus shownin FIG. 9, taken of the portion enclosed in the circle labeled “19” inFIG. 9.

FIG. 20 is a close-up side cross-sectional view of the apparatus shownin FIG. 11, taken of the portion enclosed in the circle labeled “20” inFIG. 11.

FIG. 21 is a close-up side cross-sectional view of the apparatus shownin FIG. 17, taken of the portion enclosed in the circle labeled “21” inFIG. 17.

FIG. 22 is a side cross-sectional view of the apparatus of FIGS. 1-21,the apparatus shown in a seventh condition.

FIG. 23 is a top plan view of the apparatus of FIGS. 1-20, the apparatusshown in the seventh condition.

FIG. 24 is a top perspective view of the cover of FIGS. 1-6.

FIG. 25 is a bottom perspective view of the cover of FIGS. 1-6 and 24.

FIG. 26 is a top cross-sectional view of a portion of an infusionassembly according to another embodiment of the present disclosure.

FIG. 27 is a close-up side cross-sectional view of an exemplarymicroneedle array that can be employed with the apparatus of FIGS. 1-25,the microneedle array shown with the microneedles pointing upwardly.

DETAILED DESCRIPTION

Before any embodiments of the present disclosure are explained indetail, it is to be understood that the invention is not limited in itsapplication to the details of construction and the arrangement ofcomponents set forth in the following description or illustrated in thefollowing drawings. The invention is capable of other embodiments and ofbeing practiced or of being carried out in various ways. Also, it is tobe understood that the phraseology and terminology used herein is forthe purpose of description and should not be regarded as limiting. Theuse of “including,” “comprising,” or “having” and variations thereofherein is meant to encompass the items listed thereafter and equivalentsthereof as well as additional items. Unless specified or limitedotherwise, the terms “mounted,” “supported,” and “coupled,” andvariations thereof, are used broadly and encompass both direct andindirect mountings, supports, and couplings. It is to be understood thatother embodiments may be utilized, and structural or logical changes maybe made without departing from the scope of the present disclosure.Furthermore, terms such as “front,” “rear,” “top,” “bottom,” and thelike are only used to describe elements as they relate to one another,but are in no way meant to recite specific orientations of theapparatus, to indicate or imply necessary or required orientations ofthe apparatus, or to specify how the invention described herein will beused, mounted, displayed, or positioned in use.

The present disclosure generally relates to microneedle injectionapparatuses and methods of using same. Apparatuses of the presentdisclosure can include an array of microneedles that can be applied toskin (or a biological membrane) to treat the skin (i.e., create smallholes or perforations or micropores in the skin) and can also deliver anactive agent to the skin. Apparatuses of the present disclosureparticularly include an inverted actuator for actuating release of amicroneedle array holder, to which a microneedle array can be coupled,to allow the microneedle array to impact and penetrate a patient's skinwhen desired. Such an actuator can be movable with respect to thehousing and the microneedle array holder (e.g., when the microneedlearray holder is in a retracted position) between a first position and asecond position to cause the microneedle array holder to move from aretracted position to an extended position in which the microneedlearray is positioned to contact the patient's skin. Particularly, inapparatuses of the present disclosure, at least a portion of theactuator can be located adjacent a base of a housing of the apparatus,i.e., on a skin-facing side of the apparatus, and can be actuated inresponse to the apparatus being pressed toward or onto the skin surface.Such a configuration is referred to herein as an ‘inverted actuator.’Various advantages of employing an ‘inverted actuator’ are described ingreater detail below.

Some embodiments of apparatuses of the present disclosure can beconfigured to be activated by a single actuation to automatically andreliably penetrate (or inject) a patient's skin with a microneedle array(e.g., a hollow microneedle array) and then automatically release anddispense thereto a stored fluid (e.g., an active agent) from a reservoir(e.g., a ready-to-use drug cartridge) in a controlled manner from anon-board infusion device into the skin via the microneedles. That is, insome embodiments, the inverted actuator can be configured to initiateboth injection and infusion without requiring the user to perform anyadditional steps after the single initial actuation.

The phrase “hollow microneedle” refers to a specific microscopicstructure that includes a lumen formed therein. The hollow microneedlesof the present disclosure are designed for piercing the stratum corneumto facilitate the delivery of active agents through the skin, e.g., viaeach lumen. By way of example, microneedles can include needle orneedle-like structures, as well as other structures capable of piercingthe stratum corneum and delivering the active agent. Additional detailsabout microneedles that can be employed with the apparatuses of thepresent disclosure are described in greater detail below.

Some embodiments of apparatuses of the present disclosure can beconfigured to appropriately time and stage a sequence of eventsfollowing actuation, such that, e.g., the microneedles are in place,penetrating the skin, before the active agent begins to be dispensed orreleased from the on-board infusion device. For example, in someembodiments, apparatuses of the present disclosure can include aninjection assembly or device that includes a microneedle array holder,and an infusion assembly or device that includes a cartridge thatdefines a reservoir configured to contain an active agent. An actuatorcan be actuated to cause the injection device to inject microneedlesinto the skin and to initiate infusion of the active agent from theinjection device through the injection device into the skin. In someembodiments, at least a portion of the infusion device can hold theinjection device in a retracted position until the actuator causes theinfusion device to move and release the injection device. By way ofexample only, and as described in greater detail below, the actuator canbe moved from a first position to a second position, which releases ashuttle of the infusion device that holds and carries the cartridge,which in turn releases at least a portion of the injection device (e.g.,the microneedle array holder). In some embodiments, the shuttle cancontinue moving after the injection device penetrates the skin to movethe cartridge to an infusing position where the reservoir of thecartridge is in fluid communication with a fluid path (e.g., includinghollow microneedles penetrating the skin). The active agent can then beforced out of the reservoir of the cartridge into the fluid path todeliver the active agent to the skin.

Apparatuses of the present disclosure may be useful when applied to theskin as a “pretreatment” step, that is, when applied to the skin todisrupt the stratum corneum layer of skin and then removed. Thedisrupted area of skin may then be useful for allowing enhanced deliveryof a topical composition (e.g., a solution, a cream, a lotion, a gel, anointment, or the like) or patch comprising an active agent that isapplied to the disrupted area. Apparatuses of the present disclosure mayalso be useful when the microneedles are provided with a dried coatingcomprising an active agent that dissolves from the microneedles afterthey are inserted into the skin. As a result, apparatuses of the presentdisclosure may have utility for enhancing delivery of molecules to theskin, such as in dermatological treatments, vaccine delivery, or inenhancing immune response of vaccine adjuvants. Furthermore, in someembodiments, the active agent may be applied to the skin (e.g., in theform of a solution that is swabbed onto the skin surface, or as a cream,lotion, gel, ointment, or the like, that is rubbed into the skinsurface) prior to applying the microneedles of the apparatuses of thepresent disclosure.

When a patch is applied to the treated or disrupted site, the patch canbe provided in a variety of forms and can include a drug reservoircomprising an active agent for delivery to the treated site. Anytransdermal patch suitable for the continuous transdermal delivery of atherapeutically effective amount of an appropriate medicament may beused. Suitable transdermal patches include gelled or liquid reservoirs,such as in U.S. Pat. No. 4,834,979 (Gale), so-called “reservoir”patches; patches containing matrix reservoirs attached to the skin by anadjacent adhesive layer, such as in U.S. Pat. No. 6,004,578 (Lee etal.), so-called “matrix” patches; and patches containingpressure-sensitive adhesive (PSA) reservoirs, such as in U.S. Pat. No.6,365,178 (Venkateshwaran et al.), U.S. Pat. No. 6,024,976 (Miranda etal.), U.S. Pat. No. 4,751,087 (Wick) and U.S. Pat. No. 6,149,935 (Chianget al.), so-called “drug-in-adhesive” patches, the disclosures of whichare hereby incorporated by reference. In some embodiments, the drugreservoir can be provided in the form of a matrix layer containing drug,the matrix layer being adhered to a skin-contact adhesive of the patch.Such a matrix may be an adhesive layer. Alternatively, the matrix layermay be non-adhesive or weakly adhesive and rely upon the surrounding rimof skin-contact adhesive on an adhesive patch to secure the patch inplace and keep the drug reservoir in contact with the skin surface.

In another embodiment, the drug reservoir can be provided in the form ofsolid particles embedded on the surface or within the skin-contactadhesive of the patch. In particular, these particles may behydrophilic, so that contact with aqueous fluid exposed at the surfaceof the treated skin will cause them to dissolve or disintegrate, thusreleasing drug into the skin.

In another embodiment, the drug reservoir can be provided within theskin-contact adhesive of the patch. The drug may be mixed with theskin-contact adhesive prior to forming the patch or it may be applied tothe skin-contact adhesive of the patch in a separate process step.Examples of suitable methods for applying drug to an adhesive layer maybe found in U.S. Patent Application Publication No. 2003/054025 (Cantoret al.) and U.S. Pat. No. 5,688,523 (Garbe et al.), the disclosures ofwhich are hereby incorporated by reference.

The length of time between (i) treatment of the skin with microneedlesto increase permeability and (ii) placement of the active agent incontact with the treated skin area may vary. In some embodiments, thislength of time can be kept to a minimum in order to avoid anypossibility of the skin barrier reforming through a healing process. Theminimum length of time can be generally governed by the time it takes toremove the apparatuses of the present disclosure from the skin and applythe active agent, for example, by swabbing on a solution, rubbing in acream or lotion, remove the liner of a patch and applying its adhesiveover the treated site (e.g., if a patch is being employed), etc. Thistime may be less than about 1 minute, less than about 30 seconds, lessthan about 10 seconds, or less than about 5 seconds. There is no reason,however, that this time cannot be extended to many minutes or hours ifso desired. It is generally known that the length of time that the skinwill remain increasingly permeable after treatment depends on the typeof treatment and whether the skin is occluded or not after treatment. Insome instances, increased permeability can be maintained for up toseveral days as long as the treated site remains occluded and even inthe absence of occlusion the skin may have increased permeability for upto several hours. Thus, if it presented some convenience or clinicalbenefit, one could treat the site and delay delivery of an activeagent/ingredient by wearing some type of dressing over the treated siteuntil such time as one desired to begin delivery of the active agent, atwhich time the active agent could be applied to the treated skin.

In discussing the apparatuses of the present disclosure, the term“downward,” and variations thereof, is sometimes used to describe thedirection in which microneedles are pressed into skin, and “upward” todescribe the opposite direction. However, those of skill in the art willunderstand that the apparatuses can be used where the microneedles arepressed into skin at an angle to the direction of the earth's gravity,or even in a direction contrary to that of the earth's gravity, andthese terms are only used for simplicity and clarity to describerelative directions.

FIGS. 1-25 illustrate a microneedle injection apparatus 100 according toone embodiment of the present disclosure. As shown, in some embodiments,the apparatus 100 can include an injection assembly (or device) 101 andan infusion assembly (or device) 103, which can be an on-board infusiondevice. Even though the illustrated embodiment includes both theinjection assembly 101 and the infusion assembly 103, in someembodiments, the apparatus 100 can include only the injection assembly101, and does not include an on-board infusion device such as theinfusion assembly 103 that houses an active agent to be delivered to theskin via hollow microneedles.

The phrase “on-board infusion device” generally refers to an assembly ordevice capable of delivering an active agent to the microneedles of theinjection assembly 101 for delivery to a patient's skin that forms aportion of, or is coupled to, and is operable with the injectionassembly 101.

In some embodiments, the apparatus 100 can be referred to as a“controlled fluid release apparatus.” In addition, the injectionassembly 101 can also be referred to as an “applicator” or a“microneedle applicator;” and the infusion assembly 103 can also bereferred to as a “fluid storage and delivery system or assembly.”

The apparatus 100 can further include a housing 102; an actuator 104; amicroneedle array holder 106 configured to hold and carry a microneedlearray 107 comprising a plurality of microneedles 108; a cartridge 110defining a reservoir 111 configured to contain an active agent; and acover 113. As shown in FIGS. 1, 2, 4 and 5, in some embodiments, thehousing 102 can include a ridged or texturized surface or portion 117 tofacilitate manually grasping and/or manipulating the apparatus 100.

In some embodiments, the cartridge 110 can be installed bymanufacturers, assemblers, or users. In addition, the cartridge 110 andthe microneedle array 107 can be replaced, thereby permitting reuse ofthe apparatus 100. Replaceable cartridges may provide an advantage ofbeing able to be cleaned, sterilized, filled, and refilled as comparedto microneedle devices having fixed or dedicated cartridges that areintegrally formed therewith.

As shown in FIG. 3, the injection assembly 101 can include themicroneedle array holder 106 and a microneedle array 107 (i.e., whencoupled to the microneedle array holder 106), and the infusion assembly103 can include the cartridge 110. In some embodiments, the apparatus100 can further include a fluid path 123 that is in fluid communicationwith or includes the microneedle array 107 (e.g., any surfaces ormanifolds thereof, as well as the hollow microneedles 108), when themicroneedle array 107 is coupled to the microneedle array holder 106. Asa result, the fluid path 123 can deliver an active agent to and throughthe hollow microneedles 108. Such a fluid path 123 can provide fluidcommunication between the injection assembly 101 and the infusionassembly 103 and therefore, in some embodiments, can be described asforming a portion of either assembly, or as a connection between theassemblies.

In some embodiments, at least a portion of the fluid path 123 can beformed by a conduit or channel positioned to fluidly connect thecartridge 110 and the microneedles 108. In some embodiments, thatconduit or channel can be provided by flexible tubing 129 (see FIGS. 3,4 and 6). In some embodiments, one end of such tubing can be coupled tothe microneedle array 107 and can travel with the microneedle array 107(and microneedle array holder 106). Such flexible tubing 129 can allow apiercing element 175 that is in fluid communication with the fluid path123 and is configured to pierce or puncture the cartridge 110 to remainin a fixed location within the housing 102. As such, the piercingelement 175 need not travel with the microneedle array 107 and holder106. Such tubing 129 can be formed of a variety of materials, including,but not limited to, polymeric materials, such as polypropylene,polyethylene, silicone, other suitable polymeric materials, or acombination thereof. However, in some embodiments, the piercing element175 can be fixedly coupled to the holder 106, the apparatus 100 need notinclude the flexible tubing 129, and the piercing element 175 can bemovable in the housing 102 with the microneedle array 107 and the holder106.

The infusion assembly 103 can further include a shuttle 125 configuredto hold and carry the cartridge 110 into fluid communication with thefluid path 123. The actuator 104 can be operable to actuate injection,and, in some embodiments, can further actuate movement of the shuttle125 (and, accordingly, the cartridge 110) and infusion of the activeagent into the fluid path 123 and out the hollow microneedles 108.

In some embodiments, the microneedles 108 can be configured to treatskin (i.e., create small holes or perforations or micropores in theskin) and/or deliver an active agent via skin, particularly, mammalianskin, and particularly, transdermally. Various microneedles that can beemployed in apparatuses and methods of the present disclosure aredescribed in greater detail below. In embodiments in which themicroneedles 108 are hollow and configured to deliver an active agent,each hollow microneedle 108 includes a lumen 127 (see FIGS. 14 and 15).While a “plurality of microneedles” 108 is described in the presentdisclosure, it should be understood that not all of the microneedles 108in a given array 107 are required to penetrate the skin (or to be coatedwith an active agent in embodiments in which the microneedles 108include a coating) in a given use.

The term “transdermally,” and variations thereof, is generally used torefer to any type of delivery of an active ingredient that crosses anyportion of skin. That is, transdermally can generally include systemicdelivery (i.e., where the active ingredient is transported across, orsubstantially through, the dermis such that the active ingredient isdelivered into the bloodstream), as well as intradermal delivery (i.e.,where the active ingredient is transported partially through the dermis,e.g., across the outer layer (stratum corneum) of the skin, where theactive ingredient is delivered into the skin, e.g., for treatingpsoriasis or for local anesthetic delivery). That is, transdermaldelivery as used herein includes delivery of an active ingredient thatis transported across or through at least a portion of skin (but notnecessarily all of the layers of skin), rather than merely beingtopically applied to an outer layer of the skin.

In some embodiments, the housing 102 can be self-contained and compactlyconstructed to provide a relatively low profile and small footprint for,among other factors, ease of use and patient comfort. The term“footprint” generally refers to the surface area occupied by an item(e.g., the apparatus 100), e.g., on a skin surface. The footprint of agiven item can be thought of as the area taken up by an outline of theoutermost dimensions of the item. In some embodiments, “low profile” canrefer to an apparatus 100 that is generally wide in relation to itsheight. That is, a “low profile” device can be one that has a dimensionthat extends along the skin surface that is greater than a dimensionwhich extends generally normal to (and away from) the skin surface. Saidanother way, “low profile” can refer to a device having a skin-paralleldimension that is greater than its skin-normal dimension.

As shown, the apparatus 100, and the housing 102, can be elongated alonga longitudinal axis L (see, e.g., FIGS. 1 and 2) and can be configuredto be oriented substantially parallel with respect to a skin surfacewhen in use. Such a configuration can provide a low profile for theapparatus 100. A low profile can reduce the likelihood of themicroneedles 108 becoming dislodged during penetration and/or infusionand can facilitate hands-free wear. While designing the apparatus 100such that the longitudinal axis L will be oriented generally parallel toa patient's skin surface during use can provide a low-profile andcompact design, other orientations can be employed.

In some embodiments, the housing 102 can be formed of more than oneportion. In some embodiments, the housing 102 can include a first (orupper) portion 120 adapted to be coupled (e.g., removably orpermanently) to a second (or lower) portion 122, such that the firstportion 120 can function as a cover for the second portion 122. At leasta portion of the housing 102 (e.g., the first portion 120) can includeone or more light-transmissive windows 124, which in some embodiments,can allow a user to observe the progress of at least a portion of theinfusion process. For example, as shown in FIGS. 18 and 23 and describedin greater detail below, in some embodiments, the infusion assembly 103can include one or more indicators 126 for indicating the progress ofinfusion, and such indicators 126 can be visible via the window 124. Thewindow(s) 124 need not be entirely transparent but at least partiallytransmissive to wavelengths in the visible spectrum (i.e., about 400 nmto about 700 nm) to allow for visual detection of the indicator(s) 126via the window(s) 124.

The second portion 122 of the housing 102 can be configured to hold andretain the injection assembly 101 and the infusion assembly 103. Each ofthe first portion 120 and the second portion 122 of the housing caninclude one or more retaining walls 105. The first portion 120 and thesecond portion 122 of the housing 102 can be configured to be coupledtogether by a variety of coupling means, including, but not limited to,press-fit engagement (also sometimes referred to as “friction-fitengagement” or “interference-fit engagement”), snap-fit engagement,magnets, hook-and-loop fasteners, adhesives, cohesives, clamps,stitches, staples, screws, nails, rivets, brads, crimps, detents,welding (e.g., sonic (e.g., ultrasonic) welding), any thermal bondingtechnique (e.g., heat and/or pressure applied to one or both of thecomponents to be coupled), other suitable coupling means, orcombinations thereof. By way of example only, in the embodiment of FIGS.1-25, the first portion 120 and the second portion 122 are configured tobe ultrasonically welded together. In addition, the housing 102 is shownas being split along its length into the first portion 120 and thesecond portion 122; however, other configurations are possible that alsofacilitate assembly and/or use of the apparatus 100.

In some embodiments, the housing 102 (e.g., the second portion 122 ofthe housing 102) can include a base 112 (see, e.g., FIGS. 3-5)configured to be positioned toward a skin surface 50 (see, e.g., FIG.7). The base 112 may be configured to touch the skin surface 50 duringinjection and/or infusion and may include a skin-contact adhesive.However, the base 112 of the embodiment illustrated in FIGS. 1-25 doesnot include an adhesive and is a non-adhesive surface. The base 112 ofthe housing 102 can extend along the entire length of the housing 102,but the base 112 of the housing 102 referenced herein is particularlyreferring to the base 112, or portion thereof, that is located adjacentthe injection assembly 101 and the actuator 104 that projects outwardlywith respect to the base 112, as described in greater detail below.Particularly, the base 112 of the housing 102 referenced herein isgenerally provided by or defined by a protrusion 119 that protrudes(e.g., downwardly) relative to the remainder of the housing 102 (seeFIGS. 4 and 5).

In the accompanying figures, it appears that a rear or tail end of theapparatus 100 (e.g., adjacent the infusion assembly 103 and oppositewhere the injection assembly 101 is located) is raised off of the skinsurface 50. While this may be the case, it is certainly possible thatthe tail end of the apparatus 100 would also rest against the skinsurface 50 in use. For example, the rear end of the apparatus 100 can beangled down toward the skin 50 to facilitate resting the rear end on theskin 50. In addition, in some embodiments, the base 112 of the housing102 in that region (or extending along the length of the apparatus 100)can further include a skin-contact adhesive and can be adhered to theskin. In addition, the protrusion 119 is shown by way of example only;however, it should be understood that the apparatus 100 can beconfigured not to include such a protrusion 119, and in someembodiments, the entire base 112 of the housing 102 can be flush withthe skin 50 or be configured to be adhered to the skin, e.g., afteractuation.

The housing 102 can further include or define a cavity (or chamber, orpocket, or recess, etc.) 114. As shown, the base 112 can define anopening 115 that opens into the cavity 114. Said another way, the cavity114 can extend through the base 112 to define the opening 115. Thehousing 102, and particularly, the cavity 114 (or a portion thereof) canbe configured to house at least a portion of the microneedle arrayholder 106 and the microneedle array 107 (e.g., when coupled to theholder 106), i.e., prior to application of the microneedles 108 to theskin 50.

The microneedle array holder 106 can be configured to be at leastpartially located in the cavity 114 of the housing 102 and can beconfigured to hold a microneedle array 107 within the cavity 114 of thehousing 102. The microneedle array holder 106 can also be movable withrespect to the housing 102 (i.e., with respect to the opening 115 in thehousing 102) to deliver the microneedles 108 to a substrate of interest(e.g., skin). As shown in FIG. 6, the microneedle array holder 106 caninclude a first (or bottom) side (or base) 121 that can be configured tobe positioned toward a skin surface, i.e., skin-facing, and which can beconfigured to receive the microneedle array 107. By way of example only,a microneedle array 107 can be coupled (e.g., removably coupled) to themicroneedle array holder 106 by a variety of coupling means, includingbut not limited to, press-fit engagement (also sometimes referred to as“friction-fit engagement” or “interference-fit engagement”), snap-fitengagement, magnets, hook-and-loop fasteners, adhesives, cohesives,clamps, stitches, staples, screws, nails, rivets, brads, crimps,detents, welding (e.g., sonic (e.g., ultrasonic) welding), any thermalbonding technique (e.g., heat and/or pressure applied to one or both ofthe components to be coupled), other suitable coupling means, orcombinations thereof.

The “microneedle array” 107 can include the microneedles 108 and anysupporting structure or substrate used to support the microneedles 108and/or to couple the microneedle array 107 to other structures orcomponents of the apparatus 100, such as the microneedle array holder106. For example, in some embodiments, the “microneedle array” 107 caninclude a substrate (or “carrier,” or “base”) 109 from which themicroneedles 108 protrude, as well as additional layers or carriers. Inthe embodiment illustrated in FIGS. 1-25, the microneedles 108 areintegrally formed with the substrate 109. However, it should beunderstood that additional layers can be employed in the microneedlearray 107, and other suitable configurations are possible. For example,in some embodiments, the microneedles 108 can be formed directly intothe substrate 109 which can then be coupled (e.g., mechanically andfluidly) to a base or additional layer.

In some embodiments, the apparatus 100 does not include the microneedlearray 107, but rather, the apparatus 100 can be configured to hold themicroneedle array 107 and to deliver the microneedle array 107 to theskin according to specified parameters, e.g., at a predetermined impactvelocity and/or force. Such specified parameters, for example, can beused to ensure delivery of the microneedles 108 to a predetermined depthof penetration.

The microneedle array 107 (e.g., the substrate 109) can include a firstside 116 comprising the microneedles 108 and a second side 118 oppositethe first side 116. The first side 116 can include a first major surface(e.g., defined by the substrate 109 in the illustrated embodiment) fromwhich the microneedles 108 protrude. The first side 116 can be orientedtoward the base 112 of the housing 102 (i.e., positioned to face theskin surface 50). That is, a microneedle array 107 can be coupled to themicroneedle array holder 106 such that the second side 118 faces themicroneedle array holder 106, and the first side 116 is oriented towardthe base 112 of the housing 102, i.e., positioned to face the skinsurface 50, or be “skin-facing.”

The housing 102, the actuator 104, the microneedle array holder 106and/or the microneedle array 107 (e.g., the substrate 109), the cover113, and the shuttle 125 can be formed of a variety of materials,including but not limited to, thermoset plastics (e.g., acetal resinavailable under the trade designation DELRIN® DuPont Corporation,Wilmington, Del.; other suitable thermoset plastics, or combinationsthereof), thermoplastics (e.g., polyethylene, polypropylene, othersuitable thermoplastics, or combinations thereof), or metals (e.g.,stainless steel, aluminum, other suitable metals, or combinationsthereof), or combinations thereof.

The actuator 104 can include an inner portion 130 configured to bereceived in (or extend into) the cavity 114 of the housing 102 and tointeract and/or engage with the injection assembly 101 and, in someembodiments, the infusion assembly 103. The actuator 104 can furtherinclude an outer portion 132 coupled to the inner portion 130 andconfigured to extend out of the cavity 114 of the housing 102 andthrough the opening 115 of the housing 102, such that the outer portion132 can protrude outwardly of the housing 102 and at least partiallyreside on the exterior of the housing 102 to allow a user to manuallymanipulate and control the actuator 104. For example, as shown, in someembodiments, the outer portion 132 can include or function as a buttonor other manually engageable portion or element. The outer portion 132is illustrated by way of example as being a push-button. By way offurther example, the inner portion 130 and the outer portion 132 of theactuator 104 of FIGS. 1-25 are integrally formed.

The actuator 104 can be movable with respect to the housing 102 (e.g.,with respect to the opening 115 in the base 112 of the housing 102) andthe microneedle array holder 106 between a first position P₁ (see FIGS.3-5, 7 and 8) and a second position P₂ (see FIGS. 9-13, 16-17 and 22) tocause the microneedle array holder 106 to move, respectively, between

-   -   (i) a first, retracted position H₁ (see, e.g., FIGS. 3, 4 and        7-12), in which the microneedle array 107 (when coupled to the        microneedle array holder 106) is recessed within the housing 102        (and/or the actuator 104, as described below), such that the        microneedle array 107 does not contact the skin 50 when the        apparatus 100 is positioned on the skin 50; and    -   (ii) a second, extended (or “impact” or “treatment”) position H₂        (see, e.g., FIGS. 15-17 and 22), in which at least a portion of        the microneedle array 107 (when coupled to the microneedle array        holder 106) is positioned to contact the skin 50 (e.g., via the        opening 115) when the apparatus is positioned on the skin 50.

In some embodiments, movement of the holder 106 from the retractedposition H₁ to the extended position H₂ can be dampened by one or moredampeners or shock-absorbing elements or materials, which is illustratedin FIGS. 13-15 and described below with respect to a dampener 163, asshown in FIGS. 6, 14 and 15.

As shown, in some embodiments, the actuator 104 can be movable from itsfirst position P₁ to its second position P₂ against the bias of abiasing element 128. As such, the actuator 104 can be biased in itsfirst position P₁ (e.g., downwardly) and can require a user to overcomethe bias of the biasing element 128 to actuate the apparatus 100. Thatis, the biasing force presented by the biasing element 128 representsthe force a user would need to overcome in order to actuate theapparatus 100. This biasing force can be controlled so as not to be toohigh or too low. If the biasing force is too low, the apparatus 100 maybe too sensitive and the apparatus 100 may be prematurely actuated,e.g., when a user merely intends to adhere the apparatus 100 to the skin50. However, if the biasing force is too high, the apparatus 100 may notbe able to be actuated by pressing it on soft skin. In some embodiments,the biasing force (e.g., provided by the biasing element 128), andtherefore, also the actuation force of the apparatus 100 can be at least5 N, in some embodiments, at least 6 N, and in some embodiments, is 8 N.In some embodiments, the biasing force (and hence, the actuation force)can be no greater than 15 N, in some embodiments, no greater than 12 N,and in some embodiments, no greater than 10 N.

As shown, the microneedle array holder 106 can be movable between theretracted position H₁ and the extended position H₂ independently of anyportion of the infusion assembly 103, such as the cartridge 110 and theshuttle 125, which can minimize the amount of structure that needs to bemoved to impact the skin 50 with the microneedles 108. That is, theinjection assembly 103, and portions thereof, is generally not movablewith the microneedle array holder 106 between the retracted H₁ and theextended position H₂. As a result, the injection assembly 101 can bedecoupled from and operate separately of the infusion assembly 103, eventhough both the injection assembly 101 and the infusion assembly 103 canform a portion of the overall apparatus 100, allowing each assembly tobe dedicated to their respective functions.

In some embodiments, the infusion assembly 103 (e.g., the shuttle 125and the cartridge 110) can be configured not to move independently ofthe housing 102 any appreciable amount in a direction oriented normal orsubstantially normal with respect to the skin surface 50. That is, insome embodiments, the infusion assembly 103 can be configured not tomove independently of the housing 102 toward or away from the skinsurface 50 by any appreciable amount. As in the illustrated embodiment,in some embodiments, the infusion assembly 103 may move toward the skinsurface 50 with the housing 102 as the apparatus 100 is actuated,without the infusion assembly 103 moving separately from the housing 102in this direction. In some embodiments, the infusion assembly 103 can belocated in a portion (e.g., an elongated portion, such as a handle orextension) of the apparatus 100 that can be pressed toward the skinsurface 50 along with the remainder of the apparatus 100 when theapparatus 100 is pressed toward the skin surface 50 to actuate theactuator 104. Even in such embodiments, the infusion assembly 103 can beconfigured not to move relative to the housing 102 in a direction towardor away from the skin surface 50.

The first, retracted position H₁ and the second, extended position H₂can be spaced a distance from one another along an actuation axis A′(see FIGS. 3, 7 and 16), such that the microneedle array holder 106 ismovable along the actuation axis A′, e.g., relative to the housing 102and the actuator 104 (e.g., after the actuator 104 has been moved to itssecond position P₂), between the first, retracted position H₁ and thesecond, extended position H₂.

The actuation axis A′ can generally be oriented substantially normalwith respect to the skin surface 50 (and the first side 121 of theholder 106, as well as the first side 116 of the microneedle array 107when coupled to the holder 106), but this need not be the case. Rather,in some embodiments, the actuation axis A′ can be arcuate or defineotherwise nonlinear path(s), etc. The actuation axis A′ simply refers tomovement between the first, retracted position H₁ and the second,extended position H₂.

The actuator 104 can further include a base 133 that is configured to bepositioned toward the skin surface 50, and a cavity (or chamber, orrecess, or pocket, or bore) 134 that extends through the base 133 of theactuator 104 to form an opening 135 (see, e.g., FIG. 7) in the base 133of the actuator 104. The base 133 can be at least partially defined bythe outer portion 132 of the actuator 104, and the cavity 134 can be atleast partially defined by the inner portion 130 that is dimensioned tobe received in the cavity 114 of the housing 102.

As can be seen by comparing FIGS. 7 and 9, in some embodiments, theactuator 104 (e.g., the base 133 thereof) can be movable with respect tothe base 112 of the housing 102, such that when the actuator 104 is inthe first position P₁, an outermost surface (e.g., the base 133) of theactuator 104 can extend beyond the base 112 of the housing 102 by afirst distance d₁ (e.g., see FIG. 7); and when the actuator 104 is inthe second position P₂, the outermost surface of the actuator 104 eitherno longer extends beyond the base 112 of the housing 102 (e.g., is flushwith, or recessed relative to, the base 112), or the outermost surfaceof the actuator 104 extends beyond the base 112 of the housing 102 by asecond distance d₂ (e.g., see FIG. 9) that is less than the firstdistance d₁. That is, in some embodiments, the actuator 104 can bemovable between the first position P₁ and the second position P₂ withrespect to the base 112 of the housing 102, into and out of the opening115 formed in the base 112 of the housing 102. Said another way, in someembodiments, when the actuator 104 is in the first position P₁, at leasta portion of the actuator 104 can protrude from or through the opening115 in the base 112 of the housing 102 and can define a first surface(e.g., the base 133) configured to be coupled to the skin surface 50.Such a first surface can include a skin-contact adhesive 150, asdescribed below.

The configuration of the actuator 104 is shown as being located on askin-facing surface of the apparatus 100, i.e., adjacent the base 112 ofthe housing 102. Said another way, the outer (engageable) portion 132 ofthe actuator 104 is shown as being located on and protruding from alower portion (i.e., the second portion 122) of the housing 102. Thatis, the actuator 104 is an example of an ‘inverted actuator,’ ascompared to conventional systems, where the actuator 104 is located onan underside of the apparatus 100. Such a configuration allows forfacile operation of the apparatus 100 and particularly allows for theactuator 104 to be moved from the first position P₁ to the secondposition P₂ in response to the apparatus 100 being pressed toward theskin surface 50 by pressing on a non-skin-facing, or upper, portion ofthe apparatus 100. Such a non-skin-facing, or upper, portion of theapparatus 100 (e.g., of the housing 102) need not be located directlyopposite the actuator 104. That is, the non-skin-facing, or upper,portion can be located in an off-axis position with respect to a centrallongitudinal or actuation axis of the actuator 104.

The term “off-axis” generally refers to a position, direction, or axisof movement, that is not aligned with the central longitudinal oractuation axis of the actuator 104. For example, the actuator 104 canmove from the first position P₁ to the second position P₂ in a firstdirection, along an actuation axis A″ (see FIG. 7), which, in theembodiment illustrated in FIGS. 1-25, is also its central longitudinalaxis. Such actuation or movement of the actuator 104 can be caused by aforce exerted along a second direction that is not directly opposite thesecond direction or that is not aligned with the actuation axis A″ ofthe actuator 104. Rather, such movement of the actuator 104 can becaused by a force that is oriented at an oblique angle with respect tothe actuation axis A″ of the actuator 104. In some embodiments, thesecond direction or axis can intersect the first direction or theactuation axis A″ of the actuator 104 (e.g., at an oblique angle), orthe second direction or axis can be parallel with respect to the centrallongitudinal axis of the actuator 104 without being directly in linewith the actuation axis A″.

By allowing for off-axis actuation of the apparatus 100, the apparatus100 can offer more reliable actuation, enhanced user comfort andenhanced ergonomics, for example, if the apparatus 100 can be actuatedwithout requiring that a user engage or manipulate a specific locationor element on the apparatus 100. For example, at least a portion (e.g.,the first (upper) portion 120 of the housing 102) can be configured tobe pressed toward the skin 50 using any portion of a hand, such as auser's palm or fist, as opposed to requiring the precise dexterity offinger manipulation. Such a configuration can provide an advantage, forexample, for arthritic and/or elderly patients. In addition, off-axisactuation allows for actuation of the apparatus 100 in a variety ofways, as opposed to only a single option, that are clearly understood bya user, e.g., by an intuitive design or configuration.

While the ‘inverted actuator’ 104 of the illustrated embodiment is shownas also providing the opening 135 through which the microneedle array107 will be deployed to impact and penetrate a skin surface, in someembodiments, an inverted actuator can still be employed, i.e., on anunderside or skin-facing side of the apparatus 100 and housing 102,without the actuator 104 also defining a cavity 134 or opening 135through which the microneedle array 107 and microneedle array holder 106move (as is the case in the illustrated embodiment, as described below).That is, in some embodiments, the actuator 104 can still be inverted butnot positioned directly adjacent the opening through which themicroneedles 108 extend when the microneedle array holder 106 is in itsextended position H₂. Particular advantages, however, can result fromemploying an actuator 104 such as that illustrated where the microneedlearray holder 106 is movable within the cavity 134 of the actuator 104 aswell, such as a compact design.

In some embodiments, as shown in the illustrated embodiment, theactuator 104 can be configured so as to be located only in a portion ofthe apparatus 100, which can localize the actuation of the apparatus 100to a precise area, even without requiring precise user manipulation toactuate the apparatus 100. For example, as shown, in some embodiments,the overall apparatus 100 can have or define a first footprint having afirst area, and the actuator 104 can have a second footprint having asecond area, and the second area can be less than the first area. Insome embodiments, the second area can be less than half (i.e., less than50%) of the first area. In some embodiments, the second area can be lessthan a quarter (i.e., less than 25%) of the first area.

As shown in FIGS. 1-6 and 24-25, the cover 113 can be configured tocover the opening 115 in the base 112 of the housing 102. As shown inFIGS. 3-6 and described in greater detail below with respect to FIGS. 24and 25, in some embodiments, the cover 113 can be a ‘dual cover’ thatincludes a first portion 140 configured to cover at least a portion ofthe base 112 of the housing 102 adjacent the opening 115, and a secondportion 142 configured to be at least partially received in the cavity114 of the housing 102 and further configured to cover the plurality ofmicroneedles 108 on the microneedle array 107. In embodiments such asthe illustrated embodiment that employ an ‘inverted actuator’ 104, thecover 113 can further be configured to cover the opening 135 to thecavity 134 of the actuator 104 (see, e.g., FIG. 3). The cover 113 (e.g.,the second portion 142 thereof) can be configured to maintain thesterility of the microneedles 108 and the fluid path 123 (i.e., inembodiments employing the infusion assembly 103). In embodiments inwhich the microneedle array 107 will be deployed via the opening 135 inthe actuator 104, the cover 113 (e.g., the first portion 140 thereof)can also be configured to cover and protect the actuator 104 prior touse, and can be used to inhibit or prevent accidental prematureactuation of the actuator 104. In embodiments in which the microneedlearray 107 will deployed via the opening 115 in the housing 102 but notnecessarily the opening 135 in the actuator 104, the cover 113 (e.g.,the first portion 140 thereof) can be configured to cover and protect atleast the portion of the base 112 of the housing 102 that is configuredto be coupled to a skin surface. The cover 113 is further described inco-pending U.S. Application No. 61/829,659, filed May 31, 2013, which isincorporated herein by reference.

As shown in FIG. 5, in some embodiments, the base 133 of the actuator104 can include the skin-contact adhesive 150 (described in greaterdetail below), and the apparatus 100 can further include an optionalrelease liner 152 (described in greater detail below), which can protectthe skin-contact adhesive 150 prior to use and during assembly, storageand shipment of the apparatus 100. The release liner 152 can be removedprior to applying the apparatus 100 to skin. The release liner 152 canbe configured to release, or can be configured to present releasecharacteristics to, the skin-contact adhesive 150, so that the apparatus100 can be coupled to the release liner 152 during storage and shipment,and can be easily separated from the release liner 152 duringapplication of the apparatus 100. By way of example only, the releaseliner 152 can include a tab 155 (see FIGS. 4 and 5) positioned tofacilitate removing the release liner 152 from the skin-contact adhesive150 when desired. As shown, the tab 155 can include one or more folds153 to allow the tab 155 to be shortened during storage but lengthenedwhen desired to facilitate removal of the release liner 152.

In use, the release liner 152 can be removed (if employed) from theskin-contact adhesive 150, and the adhesive base 133 of the actuator 104can be coupled to the skin 50. Actuation of the actuator 104 can occurimmediately following coupling of the base 133 of the actuator 104 tothe skin 150 or even substantially simultaneously with coupling the base133 to the skin 150. The base 133 of the actuator 104 can remain coupledto the skin 50 throughout injection and, optionally, infusion. As aresult, in some embodiments, the apparatus 100 can be configured to be“worn” by a patient during infusion/injection of fluid into the skin 50.In such embodiments, the apparatus 100 may be directly applied to apatient's skin 50 to accommodate ambulatory movement while keeping themicroneedles 108 at an appropriate penetration depth(s). That is, evenin embodiments in which the housing 102 itself does not include theskin-contact adhesive 150, the housing 102 (i.e., the apparatus 100 as awhole, including the actuator 104, the housing 102, and the elements ofthe infusion assembly 103) can be configured to remain coupled to theskin surface 50 after the microneedle array 107 has punctured the skin50 and during infusion. For example, in such embodiments, the housing102 can be configured to be adhered to the skin 50 via the skin-contactadhesive 150 on the actuator 104.

In some embodiments, as shown, the microneedle array holder 106 can belocated in and movable in the cavity 134 of the actuator 104 between theretracted position H₁ and the extended position H₂. As such, in someembodiments, the actuator 104 can be configured to at least partiallysurround the microneedle array 107 when the microneedle array 107 iscoupled to the holder 106, at least when the holder 106 is in theextended position H₂. In some embodiments, the actuator 104 can beconfigured such that at least a portion of the actuator 104 (e.g., theouter portion 132) surrounds the microneedle array 107 (and/or themicroneedle array holder 106) on all sides, or encircles the microneedlearray 107 (and/or the microneedle array holder 106), at least when themicroneedle array holder 106 is in the extended position H₂.

As shown in FIGS. 7 and 9, in embodiments in which the actuator 104 isinverted and located adjacent the same opening 115 through which themicroneedle array 107 will contact the skin 50, and when the actuator104 is in the first position P₁ and the microneedle array holder 106 isin the retracted position H₁, the base 133 of the actuator 104 can bepositioned a first distance x₁ from the first side (or base) 121 of themicroneedle array holder 106 (and/or the first side (or base) 116 of themicroneedle array 107)—see FIG. 7. When the actuator 104 is in thesecond position P₂ the base 133 of the actuator 104 can be positioned asecond distance x₂ from the first side (or base) 121 of the microneedlearray holder 106 (and/or the first side (or base) 116 of the microneedlearray 107)—see FIG. 9—and the second distance x₂ can be less than thefirst distance x₁. As a result, the distance between the base 133 of theactuator 104 and the first side 121 of the microneedle array holder 106(or the first side 116 of the microneedle array 107) can decrease whenthe actuator 104 is moved from the first position P₁ to the secondposition P₂.

By way of example only, in the embodiment illustrated in FIGS. 1-25, atleast a portion of the cavity 114 in the housing 102 can have the shapeof a cylindrical bore, at least a portion of the actuator 104 caninclude an annular cross-sectional shape (e.g., when the cross-sectionis taken substantially parallel with respect to the base 133), and theinner portion 130 of the actuator 104 can be substantially tubular inshape and be dimensioned to be received in the cylindrical bore-shapedcavity 114 of the housing 102. In addition, the cavity 134 defined atleast partially by the inner portion 130 of the actuator 104 can havethe shape of a cylindrical bore. By way of example only, the centrallongitudinal axes of the bore-shaped cavities 114 and 134 defined by thehousing 102 and the actuator 104, respectively, can be substantiallyaligned, and the actuation axis A′ (see FIGS. 3, 7 and 16) ofmicroneedle array holder 106 can also be substantially aligned with thecentral longitudinal axes of the cavities 114 and 134.

In some embodiments, the actuation axis A′ and the central longitudinalaxes of the cavities 114 and 134 may not all be exactly aligned but canbe substantially parallel with respect to one another. In someembodiments, the actuation axis A′ of the holder 106 can be orientedsubstantially parallel with respect to the actuation axis A″ of theactuator 104, as shown in the illustrated embodiment. Furthermore, insome embodiments, as shown, the actuation A′ of the holder 106 can besubstantially aligned (i.e., in line with) with the actuation axis A″ ofthe actuator 104.

When the microneedle array holder 106 is in the first, retractedposition H₁, the holder 106 can be recessed within the housing 102 andthe actuator 104, such that the holder 106 (and the microneedle array107, when coupled to the holder 106) does not extend beyond the base 112of the housing 102 or the base 133 of the actuator 104. The microneedlearray 107 can be movable with the holder 106 along the entire distancebetween the holder's retracted and extended positions H₁ and H₂. Thatis, when the microneedle array holder 106 is in the first, retractedposition H₁ and a microneedle array 107 is coupled to the holder 106,the microneedle array 107 can also be in a first, retracted position M₁(see, e.g., FIGS. 3, 7, 9 and 11), e.g., in which the microneedle array107 is recessed within the housing 102 and the actuator 104 such thatthe microneedle array 107 does not contact (or is not positioned tocontact) the skin surface 50 when the base 133 of the actuator 104 ispositioned on the skin surface 50. The microneedle array 107 can behoused within the cavity 114 of the housing 102 and the cavity 134 ofthe actuator 104, and can be recessed with respect to the base 112 ofthe housing 102 and the base 133 of the actuator 104 in its retractedposition M₁.

Furthermore, when the microneedle array holder 106 is in the second,extended position H₂ and a microneedle array 107 is coupled to theholder 106, the microneedle array 107 can also be in a second, extendedposition M₂ (see, e.g., FIGS. 15-17 and 22), e.g., in which at least aportion of the microneedle array 107 is positioned to contact the skinsurface 50 when the base 133 of the actuator 104 is positioned on theskin surface 50.

When the microneedle array holder 106 and the microneedle array 107 arein their respective second positions H₂ and M₂, at least a portion ofthe microneedle array 107 (and, potentially, a portion of themicroneedle array holder 106) can extend beyond the base 133 of actuator104. However, this need not be the case, and in some embodiments, it canbe preferred for this not to be the case. Rather, in some embodiments,the microneedles 108 can be positioned close enough to the base 133 ofthe actuator 104 (while still being recessed within the housing 102 andthe actuator 104 and without extending beyond the base 133 of theactuator 104), such that when the base 133 is pressed onto the skinsurface 50, the skin 50 is caused to deform or dome up through theopening 135 of the actuator 104 and into the cavity 134 to a positionwhere the skin 50 is contacted by the microneedles 108.

Portions of the housing 102 defining the cavity 114 and/or portions(e.g., the inner portion 130) of the actuator 104 defining the cavity134 can retain and/or guide the microneedle array holder 106 fordisplacement along a path generally perpendicular to the base 133 of theactuator 104 (and/or the base 112 of the housing 102), as indicated byarrow A in FIG. 7. The actuation axis A′ of the microneedle array holder106 can be generally normal or perpendicular to that of the longitudinalaxis L of the apparatus 100. While in one exemplary embodiment, themotion of holder 106 may be at substantially 90 degrees with respect tothe base 133 (and/or the base 112), it will be appreciated that thegenerally normal path may deviate from 90 degrees to assume orientationsthat can penetrate deep enough to deliver an intended dosage.

The microneedle array holder 106 (and a microneedle array 107 coupledthereto) can be movable from the retracted position H₁ (and M₁) to theextended position H₂ (and M₂) by a first stored energy device 138 thatis actuatable to release its potential energy for applying force to themicroneedle array holder 106 in a direction generally normal to the base133 (and/or the base 112), for example, downwardly, toward the skinsurface 50. In some embodiments, such actuated force allows for movementof the holder 106 in a controlled manner, thereby ensuring applicationof the necessary forces for microneedles 108 to penetrate the skin of apatient. As a result, the apparatus 100 can reliably and consistentlydeliver the microneedle array 107 to the skin at a desired impactvelocity, e.g., to achieve the desired depth(s) of penetration.

In some embodiments, the first stored energy device 138 can beactuatable to apply force to the holder 106 to achieve a velocity of themicroneedle array 107 before impact (i.e., before the microneedle array107 held by the holder 106 impacts a patient's skin) ranging frombetween about 2 and about 20 m/s. More typically, the microneedle array107 can strike a patient's skin at a velocity before impact ranging frombetween about 4 and about 12 m/s, in some embodiments, at a velocitybefore impact of at least 5 m/s, and in some embodiments, at a velocitybefore impact of about 6 m/s.

In some embodiments, the first stored energy device 138 can include abiasing element (e.g., a spring), and is shown as a coil spring by wayof example only in the illustrated embodiment. However, stored energydevices of the present disclosure can include at least one stored energydevice from a group consisting of: biasing elements (e.g., springs),propellants, chemicals, motors, electrical devices, and combinationsthereof.

The microneedle array holder 106 is biased downwardly in the apparatus100, toward its extended position H₁. As a result, the microneedle array107, when coupled to the holder 106 is also biased toward its extendedposition M₁. The microneedle array holder 106 is primed, or held underload or against the bias (e.g., when a biasing element is employed asthe stored energy device 138) when in the retracted position H₁, suchthat when the microneedle array holder 106 is released from being held,the stored energy device 138 will provide the forces to move themicroneedle array holder 106 to its extended position H₂, andparticularly, at a desired velocity.

In some embodiments, a portion of the actuator 104 can hold themicroneedle array holder 106 in its retracted position H₁ until theactuator 104 has been moved to its second position P₂, at which pointthe actuator 104 no longer holds the microneedle array holder 106, andthe microneedle array holder 106 is free to be driven by the storedenergy device 138.

However, in some embodiments, as shown in the illustrated embodiment, anintermediate component, i.e., between the actuator 104 and the holder106, can be actuated to move (or be released) by moving the actuator 104to its second position P₂, and when that intermediate component isactuated or allowed to move, it moves to a position in which it nolonger retains the holder 106 in its retracted position H₁, and themicroneedle array holder 106 is free to be driven by the stored energydevice 138. As a result, in some embodiments, the microneedle arrayholder 106 is held within the housing 102 in its retracted position H₁by an element, component or structure of the apparatus 100 other thanthe actuator 104.

In the illustrated embodiment, that intermediate component is an elementof the infusion assembly 103, namely, the shuttle 125. The shuttle 125can be movable (e.g., substantially along the longitudinal axis L of theapparatus 100) between:

-   -   (i) a first, non-infusing, position S₁ (see, e.g., FIGS. 3, 4        and 7-10) in which the reservoir 111 of the cartridge 110 is not        in fluid communication with the fluid path 123 (i.e., in which        the cartridge 110 is fluidly isolated), and    -   (ii) a second, infusing, position S₂ (see, e.g., FIGS. 17        and 22) in which the reservoir 111 of the cartridge 110 is in        fluid communication with the fluid path 123.

As a result, in some embodiments, movement of the actuator 104 to itssecond position P₂ (i.e., “actuation” of the actuator 104) can actuateboth (i) movement of the shuttle 125 (i.e., the cartridge 110) to itssecond position S₂ and movement of the microneedle array holder 106 tothe extended position H₂.

Because the shuttle 125 of the illustrated embodiment is configured tohold and carry the cartridge 110, the first and second position S₁ andS₂ of the shuttle 125 also define positions of the cartridge 110. As aresult, the positions of the shuttle described herein can also refer topositions of the cartridge 110. However, in embodiments that do notemploy the infusion assembly 103, the apparatus 100 can still include anintermediate element, i.e., the shuttle 125 that is movable in responseto movement of the actuator 104 to its second position P₂ to a secondposition S₂ in which the microneedle array holder 106 is released. Theposition at which the microneedle array holder 106 is released isdescribed below as a third position S₃ that is intermediate that of thefirst shuttle position S₁ and the second shuttle position S₂; however,in embodiments that do not include a cartridge 110 or the other elementsof the infusion assembly 103, the second position S₂ of the shuttle 125can be described as the position at which the microneedle array holder106 is released.

The shuttle 125 can be primed or held under a load in its first positionS₁ and can be biased toward its second position S₂, such that when theshuttle 125 is released by the actuator 104, the shuttle is free to moveand begins moving toward its second position S₂. Employing the separateshuttle 125 that carries the cartridge 110 and operates intermediatelybetween the actuator 104 and the microneedle array holder 106 canprovide a sequence of events that ensures a sufficient delay betweenimpact (i.e., movement of the microneedle array holder 106 to itsextended position H₂) and infusion (e.g., at least when the shuttle 125is moved to its second position S₂ where fluid communication isestablished between the reservoir 111 and the fluid path 123). That is,the microneedle array holder 106 can be moved to its extended positionH₂ before the shuttle 125 has completed its movement to its secondposition S₂. In some embodiments, as is the case in the illustratedembodiment, the shuttle 125 can begin moving to its second position S₂before the microneedle array holder 106 may reach its extended positionH₂, but the apparatus 100 can be configured such that the shuttle 125will not have fully reached its second position S₂ (i.e., the point ofestablishing fluid communication between the cartridge 110 and the fluidpath 123) before the microneedle array 107 has punctured the skin 50.

Said another way, even though the actuator 104 actuates movement of boththe shuttle 125 and the microneedle array holder 106, the microneedlearray holder 106 can be in its extended position H₂ when the shuttle 125reaches its second position S₂, such that there is a lag or delaybetween when the microneedle array 107 is inserted into the skin 50 andwhen the reservoir 111 is placed in fluid communication with themicroneedle array 107. If this were not the case, active agent couldbegin leaking out of the microneedles 108 prior to the microneedles 108penetrating the skin 50. In some embodiments, this lag can accommodate aperiod of time in which the microneedle array 107 may undergo someundulating motion as it impacts the skin 50, which can be about 8 toabout 10 milliseconds. Generally, it can be advantageous to providefluid communication between the fluid path 123 and the cartridge 110after the microneedle array 107 (and holder 106) has reached a steadystate condition and is no longer bouncing on the skin surface 50.

The shuttle 125 can be configured to movable between its first positionS₁ and its second position S₂ in a direction or along an axis that isoriented at a non-zero angle with respect to the actuation axis A′ ofthe holder 106 and/or the actuation axis A″ of the actuator 104. Thatis, in some embodiments, the microneedle array holder 106 can be movablebetween the retracted position H₁ and the extended position H₂ along afirst axis (i.e., its actuation axis A′), the actuator 104 can bemovable between the first position P₁ and the second position P₂ along asecond axis, and the shuttle 125 can be movable between the firstposition S₁ and the second position S₂ along a third axis, and the thirdaxis can be oriented at a non-zero angle with respect to one or both ofthe first axis and the second axis. Particularly, in embodimentsemploying a low profile configuration in which the shuttle 125 can beconfigured to move in a direction substantially parallel to the skinsurface 50, which can also be generally along the longitudinal axis L insome embodiments, and the third axis can be oriented substantiallyperpendicularly with respect to one or both of the first axis and thesecond axis.

The shuttle 125 can be configured to interact with the microneedle arrayholder 106 to retain the holder 106 in its retracted position H₁ untilthe shuttle 125 reaches an intermediate position (i.e., a third positionS₃—see, e.g., FIG. 13) in between the first position S₁ and the secondposition S₂ in which the microneedle array holder 106 is released frombeing held in its retracted position H₁ by the shuttle 125. FIGS. 11 and12 show the shuttle 125 after it has begun to move from its firstposition S₁, but before it has reached the third position S₃ in whichthe holder 106 is released.

Movement of the shuttle 125 between its first and second positions S₁and S₂ can be accomplished or driven by one or more stored energydevices. In the illustrated embodiment, two stored energy devices areused to fully move the shuttle 125 from the first position S₁ to thesecond position S₂. By way of example, in the illustrated embodiment, asecond stored energy device 144 (see FIGS. 3, 6, 7, 9, 11, 13, 16, 17and 22) can initiate movement of the shuttle 125, e.g., to move theshuttle 125 from the first position S₁ to the third position S₃, wherethe microneedle array holder 106 can be released from its retractedposition H₁. By way of further example, in the illustrated embodiment, athird stored energy device 146 (see FIGS. 3, 6, 7, 9 and 11, 13, 16, 17and 22) can complete movement of the shuttle 125 to its second positionS₂ wherein the reservoir 111 of the cartridge 110 is in fluidcommunication with the fluid path 123, and can further initiate andcomplete infusion of an active agent from the reservoir 111 of thecartridge 110, into the fluid path 123, and out the hollow microneedles108.

The cartridge 110 can include a piston 148 that is movable in thereservoir 111 of the cartridge 110 to force the active agent out of thecartridge 110, into the fluid path 123, and out the hollow microneedles108. The piston 148 can be in a sliding and sealing relationship withrespect to interior walls of the cartridge 110. This can provideadequate sealing for a fluid stored in an interior variable volumechamber formed between the piston 148 and an openable end 151 of thecartridge 110. The piston 148 can be moved or pressed in the cartridge110 by a plunger 149 that can be coupled to, and movable with, theshuttle 125 and the cartridge 110, until the shuttle 125 reaches itssecond position S₂, after which the plunger 149 can be movable withrespect to the housing 102, the shuttle 125, the cartridge 110, etc. todrive the piston 148 to dispense the active agent. That is, in someembodiments, the infusion assembly 103 can be configured such that thepiston 148 (and the plunger 149) is not movable in the reservoir 111with respect to the shuttle 125 until the shuttle is in its secondposition S₂. Said another way, in some embodiments, the infusionassembly 103 can be configured such that the piston 148 is inhibited orprevented from movement to its second position until the shuttle 125 isin its second position S₂.

The piston 148 and the plunger 149 can be movable together between (i) afirst (non-dispensing or non-delivery) position in which the activeagent is not being forced out of the reservoir 111 and into the fluidpath 123 (i.e., in which the active agent is contained within thereservoir 111); and (ii) a second, dispensed, position in which theactive agent is being forced out of the reservoir 111 and into the fluidpath 123.

Given the volume variability of the reservoir 111 of the cartridge 110,the cartridge 110 can be configured to accommodate any intended dosagevolume. Such a cartridge 110 may be of the type wherein pre-filled drugsare ready-to-be used. The cartridge 110 may be of the kind thatsatisfies standards, including international standards, such as theInternational Organization for Standards (ISO). In addition, a glasscylinder can be employed as the cartridge 110, which can be relativelyeasy to clean and sterilize.

The present disclosure also contemplates the use of valve mechanisms foropening the openable end 151 of the cartridge 110 for allowingtransferring of an active agent to the fluid path 123. For example, avalve member retained by the cartridge 110 may be opened from a fluidblocking or closed condition by having it cooperate with structure (notshown), such as a cannula, as the two are brought into operativeengagement. Suitable valve mechanisms include, but are not limited to,those disclosed in International Publication No. WO2005/018705 toCindrich et al.

Referring back to the piston 148, it is adapted to travel along a lengthof reservoir 111 (e.g., which can be oriented substantially along thelongitudinal axis L) until the active agent is completely (or nearlycompletely) forced or expressed therefrom. Typically, the piston 148 maybe made of materials that seal against the body of cartridge 110, butare also inert with respect to the active agent. For example, purifiedelastomeric materials such as halobutyl rubber and silicone rubbermaterials may be typically used for such pistons, but other materialssuch as non-elastomeric materials are also contemplated. In addition,the piston 148 can be made of diverse materials including laminatedconstructions. While the illustrated embodiment uses one kind of piston,others can be utilized, including those contoured to substantially matchthe interior shape of the openable end 151.

Other means to reduce void space in the cartridge are contemplated. Forexample, small spherical objects can be included in the reservoir 111.When the piston 148 moves forward and pushes the active agent out of thecartridge 110, the small spherical objects can also be pushed forwardinto the neck of the cartridge 110 and around the piercing element 175.The spherical objects are preferably larger than the fluid path 123 inthe piercing element 175 so as to avoid plugging the fluid path 123.Instead, the spherical objects can pack around the piercing element 175and displace active agent in the cartridge neck space. The sphericalobjects can be made of metal, plastic, glass, ceramic, or other materialthat is compatible with the active agent in the reservoir 111.

The cartridge 110 has longitudinal axis that can be generally orientedalong the longitudinal axis L of the apparatus 100 and/or that can beoriented generally parallel to the skin 50 in use. In other embodiments,the cartridge 110 can be disposed at non-zero angles relative to theskin 50. In embodiments wherein a low profile for the apparatus 100 (orat least the infusion assembly 103 thereof) is desired, the longitudinalaxis of the cartridge 110 can be generally parallel to the major plane(e.g., of the first side 116) of the microneedle array 107 (when coupledto the microneedle array holder 106). The cartridge 110 can be a glassdrug cartridge (e.g., that is transparent). Such a glass drug cartridgemay be of a commercially available type, such as from Schott NorthAmerica, Elmsford, N.J., USA, and West Pharmaceutical Services, Inc. ofLionsville, Pa., USA. Other kinds of cartridges having similarproperties are well within the scope of the disclosure.

When made of glass, the cartridge 110 may also be advantageous in regardto enhancing the versatility of the delivery systems of the presentdisclosure. One potential advantage is that the cartridge 110 canconform to the sizes and shapes already familiar in the pharmaceuticalfield that can be, e.g., readily fillable using commercial equipment. Inaddition, because the cartridge 110 may be packaged separately from theapparatus 100, users may be able to use custom reservoirs and easilyinstall them in the apparatus 100 at the point of use. As shown in FIG.6, in some embodiments, a door or cover 147 can be employed to allowdirect access to the location of the infusion assembly 103 in which thecartridge 110 can be positioned. Moreover, by being able to use knowndrug cartridges, patients are able to use a wide variety of drugs anddosages dispensed in a manner particularly tailored to them and not bedependent on a manufacturer of the dispensers having fixed cartridges.

A typical glass drug cartridge that may be employed with the apparatusesof the present disclosure may have dimensions that range from 2 cm toabout 8 cm in terms of their length, and may have inner diameters thatrange from 4 mm to 12 mm. More typically, the lengths may range from 4cm to 6 cm, and the inner diameters from 6 mm to 10 mm. The presentdisclosure contemplates other dimensions depending on, for example, thevolume of the active agent to be delivered. While a transparent glassdrug cartridge may be used, other materials may also be used. Thematerials and construction of the cartridge 110 are generally compatiblewith the desired active agent to be dispensed and able to withstand thepressures generated during use.

In some embodiments, the volume of the active agent to be delivered orinfused can be at least 0.1 mL, in some embodiments, at least 0.2 mL,and in some embodiments, at least 0.5 mL. In some embodiments, thevolume can be no greater than 20 mL, in some embodiments, no greaterthan 10 mL, in some embodiments, no greater than 5 mL, and in someembodiments, no greater than 3 mL. In some embodiments, the volume canrange from 0.1 mL to 20 mL, in some embodiments, from 0.1 mL to 10 mL,and in some embodiments, from 0.1 to 5 mL. In some embodiments, thevolume can range from 0.5 mL to 3 mL.

By way of example only, in the illustrated embodiment, the same thirdstored energy device 146 that completes the movement of the shuttle 125to its second position S₂ can also initiate and complete the infusionprocess, i.e., to initiate and complete movement of the plunger 149 andthe piston 148, accordingly, to dispense the active agent.

In some embodiments, the second and third stored energy devices 144 and146 can each include a spring or biasing element, and each is shown as acoil spring by way of example only in the illustrated embodiment.However, any of the above stored energy devices can be employed for eachof the second and third stored energy devices 144 and 146. Inembodiments in which a biasing element is employed, the shuttle 125 canbe primed or held under load, e.g., against the bias of the biasingelements 144 and 146 when the shuttle is in the first position S₁.

That is, the shuttle 125 can be biased in or toward its second positionS₂. For example, the shuttle 125 can be biased by one or both of thesecond stored energy device 144 and the third stored energy device 146,e.g., if one or both of the second and third stored energy devices 144and 146 includes a biasing element. The shuttle 125 can be maintained inits first position S₁ until the actuator 104 has been moved to itssecond position P₂. By way of example, in the illustrated embodiment,the actuator 104 includes a portion that maintains the shuttle 125 inits first position S₁ until the actuator 104 has been moved to itssecond position P₂.

Specifically, in some embodiments, as shown in FIGS. 8, 10 and 12, theactuator 104 can include one or more shuttle stops (or catches, ordetents) 154 that can be movable with the actuator 104 when the actuatoris moved between its first and second positions P₁ and P₂. The apparatus100 is generally symmetrical about the longitudinal axis L. As such, theillustrated embodiment employs two shuttle stops 154—one on each side ofthe apparatus 100; however, only one is shown in FIGS. 8, 10 and 12. Itshould be understood, however, that in some embodiments, the apparatus100 can include only one shuttle stop 154. In embodiments in which morethan one shuttle stop 154 is employed, it should be understood that thedescription herein can equally apply to additional stops.

The shuttle stop 154 is configured to abut and/or engage at least aportion of the shuttle 125. As a result, the shuttle stop 154 can becoupled to or formed by at least a portion of the actuator 104, and canbe movable, with the actuator 104, between:

-   -   (i) a first position T₁ with respect to the housing 102, the        shuttle 125 and the microneedle array holder 106 (see FIG. 8) in        which the shuttle stop 154 is positioned to engage at least a        portion of the shuttle 125 to hold the shuttle 125 in its first        position S₁, and    -   (ii) a second position T₂ with respect to the housing 102, the        shuttle 125 and the microneedle array holder 106 (see FIGS. 10        and 12) in which the shuttle stop 154 is no longer positioned to        engage at least a portion of the shuttle 125 to hold the shuttle        125 in its first position S₁, such that when the shuttle stop        154 is in the second position T₂, the shuttle 125 is free to        move to its second position S₂, e.g., by the second and third        stored energy devices 144 and 146.

In FIGS. 7 and 8, the actuator 104, the shuttle 125, the microneedlearray holder 106, and the piston 148 (and the plunger 149) are all intheir respective first positions. In these respective first positions,the shuttle 125, the microneedle array holder 106, and the piston 148(and the plunger 149) can be primed or held under a load, ready to befired, i.e., driven by the stored energy devices 138, 144 and/or 146.

In FIGS. 9 and 10, the actuator 104 is in its second position P₂ and theshuttle stop 154 is in its second position T₂, but the shuttle 125 hasnot yet begun to move toward its second position S₂. In FIGS. 11 and 12,the actuator 104 is in its second position P₂ and the shuttle stop 154is in its second position T₂, and the shuttle 125 has begun to movetoward its second position S₂, but the microneedle array holder 106 hasnot yet been released from its retracted position H₁.

As shown in FIGS. 8, 10 and 12, the shuttle 125 can include one or moreextensions, prongs or projections 156 that are each configured to engageand interact with a shuttle stop 154. The extensions 156 are shown byway of example as lateral extensions that extend along the lateral sidesof the apparatus 100 and are elongated generally along the longitudinalaxis L. Each extension 156 includes a first portion (or surface, e.g., aside or front surface in the illustrated embodiment) that can be notchedor include a flange configured to engage the shuttle stop 154 of theactuator 104 until the actuator 104 has been moved out of engagementwith the shuttle 125, e.g., until the actuator 104 has been moved to thesecond position P₂, thereby moving the shuttle stop 154 to its secondposition T₂.

Each extension 156 can further include a second portion (or surface,e.g., an upper surface in the illustrated embodiment) that can beconfigured to engage with the shuttle stop 154 after the actuator 104has been moved to its second position P₂ so as to maintain the actuator104 in the second position P₂ after it has been moved to its secondposition P₂. As a result, as the actuator 104 is moved to its secondposition P₂, the shuttle 125 gets released; and the shuttle 125 can beconfigured such that as the shuttle 125 moves toward its second positionS₂, the shuttle 125 catches the actuator 104 and holds the actuator 104in its second position P₂.

Such a configuration can inhibit the actuator 104 from being forced backtoward its first position P₁ after actuation, e.g., which couldpotentially dislodge the microneedles 108 from the skin 50 during use.Accordingly, each shuttle stop 154 can include a first portion (orsurface, e.g., a side or rear surface in the illustrated embodiment)configured to inhibit movement of the shuttle 125 from its firstposition S₁ and a second portion (or surface, e.g., a lower surface inthe illustrated embodiment) configured to inhibit movement of theactuator 104 from its second position P₂ once the actuator 104 has beenmoved to its second position P₂. However, this arrangement andinteraction between the shuttle 125 and the actuator 104 is shown by wayof example only. In some embodiments, the shuttle stop 154 on theactuator 104 can be configured to engage a different element when in itssecond position P₂ to maintain the actuator 104 in its second positionP₂ after it has been moved to its second position P₂.

As shown, e.g., in FIGS. 4, 6 and 7-13, in some embodiments, themicroneedle array holder 106 can include one or more extensions orprongs 158 configured to engage one or more holder stops 160 on theshuttle 125. Similar to the shuttle stop 154 on the actuator 104, theholder stop 160 is movable with the shuttle 125, between:

-   -   (iii) a first position R₁ with respect to the housing 102, the        actuator 104, and the microneedle array holder 106 (see FIGS.        7-10) in which the holder stop 160 is positioned to engage at        least a portion of the microneedle array holder 106 (i.e., the        extension 158) to hold the microneedle array holder 106 in its        retracted position H₁, and    -   (iv) a second position R₂ with respect to the housing 102, the        actuator 104, and the microneedle array holder 106 (see FIG. 13)        in which the holder stop 160 is no longer positioned to engage        at least a portion of the microneedle array holder 106 to hold        the microneedle array holder 106 in its retracted position H₁,        such that when the holder stop 160 is in the second position R₂,        the microneedle array holder 106 is free to move toward its        extended position H₂, e.g., by the first stored energy device        138.

FIGS. 11 and 12 illustrate the shuttle 125 before it has quite reachedits intermediate third position S₃ in which the microneedle array holder106 is released and able to move toward its extended position H₂, whichis shown in FIG. 13. As mentioned above and is described in greaterdetail below with respect to FIGS. 14 and 15, FIG. 13 illustrates anoptional dampened position of the holder 106, before the holder 106 hasfully reached its extended position H₂, which is shown in FIGS. 15-17and 22.

The holder stop(s) 160 on the shuttle 125 can be coupled to or formed bya portion of the shuttle 125. By way of example only, the extension 158on the holder 106 is shown as being a vertical extension or projection.The extension 158 can be notched or include a flange (e.g., such thatthe extension 158 includes a lower surface) that is configured to abutthe holder stop 160 (e.g., an upper surface thereof). The holder stop160 can extend a predetermined distance along the longitudinal axis L ofthe apparatus 100, such that when the holder stop 160 has moved to itssecond position R₂, the extension 158 on the holder 106 has cleared theholder stop 160, is no longer in engagement with the holder stop 160,and the holder 106 is free to be driven by the first stored energydevice 138 to its extended position H₂. By further way of example, theholder stop 160 can be formed or defined by one or more extensions,prongs or projections 162. Specifically, in the illustrated embodiment,the shuttle 125 includes two extensions 162 that extend generally alongthe longitudinal axis L of the apparatus 100 and include a lower ledgeor flange that includes an upper surface that defines the holder stop160. In the illustrated embodiment, the holder stop 160 is specificallyformed by two of such ledges that the extension 158 of the holder 106rests on, or is forced against, when the holder 106 is held under loadin its retracted position H₁. That is, the extension 158 and the holderstop 160 slide relative to one another as the shuttle 125 is moved inthe housing 102 generally along the longitudinal axis L of the apparatus100 toward its second position S₂, until the holder stop 160 reaches itssecond position R₂ (i.e., until the shuttle 125 reaches its thirdposition S₃, located intermediately between its first position S₁ andits second position S₂).

As shown in FIGS. 6 and 14-15, in some embodiments, the apparatus 100can include one or more dampeners 163 positioned between the microneedlearray holder 106 and the actuator 104 (or the housing 102 in embodimentsin which the holder 106 is not moving to its extended position H₂adjacent the actuator 104). The dampeners 163 can be configured to atleast partially deform in response to the inertia of the microneedlearray holder 106 as the holder 106 is driven by the first stored energydevice 138 to its extended position H₂, thereby dampening or slowing theholder 106 as it comes to a stop in its extended position H₂. In theillustrated embodiment, the dampener 163 includes a wire formed into anincomplete circle (see FIG. 6) positioned in a recess within the cavity134 of the actuator 104 and located between the base 133 of the actuator104 and an underside of the holder 106 (see FIG. 14). FIG. 15illustrates the holder 106 at the end of its travel (i.e., with theholder 106 fully in its extended position H₂ and the microneedle array107 fully in its extended position M₂), with its guide rails resting onthe ends of guides formed within the actuator 104. The dampener 163 inFIG. 15 has been deformed and forced into a lower recess 164 by theholder 106. In the illustrated embodiment, the recess 164 into which thedampener 163 is forced is defined by the actuator 104; however, inembodiments in which the holder 106 does not travel in the actuator 104,such a recess could be provided by the housing 102 or another element ofthe apparatus 100. The illustrated dampener 163 and relativeconfiguration between the holder 106 and the actuator 104 are shown byway of example only; however, any energy or shock absorbing element ormaterial can be employed and other configurations are possible andwithin the spirit and scope of the present disclosure.

While the microneedle array 107 impacts the skin 50, the shuttle 125continues to travel along the longitudinal axis L toward its secondposition S₂ (as shown in FIGS. 17 and 22). In the illustratedembodiment, as shown in FIGS. 13, 16, 17 and 22, the indicator 126 caninclude a first portion (or “main body”) 126 a and a second portion (or“tail”) 126 b that are configured to be removably coupled together,e.g., by one or more latches or detents 166.

The second stored energy device 144 (e.g., a spring) can be locatedwithin one or more retaining walls or tubes 168 (see, e.g., FIG. 13),which are provided by, or fixedly coupled to, the housing 102. By way ofexample, the retaining wall 168 is generally tubular, generallycentrally located in the housing 102 with respect to the shuttle 125 andthe indicator 126, and oriented generally along the longitudinal axis L.The retaining wall 168 can define a recess (or bore or chamber) 173,e.g., which can receive at least a portion of the second stored energydevice 144. In addition, the first indicator portion 126 a and thesecond indicator portion 126 b of the illustrated embodiment eachinclude inner (e.g., concentric and forwardly-projecting) walls (orprongs or projections) 170 a and 170 b, respectively, that are removablycoupled together (e.g., at their respective front ends) via the latch166 and together define a generally tubular recess 172 (see FIG. 13)configured to receive the retaining wall 168. By way of example, in theillustrated embodiment, the inner wall 170 b of the second indicatorportion 126 b is formed by a series of (circumferentially-spaced) prongsconfigured to be arranged about the inner circumference defined by theinner wall 170 a of the first indicator portion 126 a when the first andsecond indicator portions 126 a and 126 b are coupled together via thelatch 166. Accordingly, the inner wall 170 a of the first indicatorportion 126 a can include a series of notches or openings configured toreceive at least a portion of the inner wall 170 b, i.e., the portion(s)of the one or more prongs forming the one or more latches 166.

As the shuttle 125, along with the indicator 126, is initially movedfrom its first position S₁ by the second stored energy device 144, theinner walls 170 a and 170 b, removably coupled by the latch 166, slideor ride along the retaining wall 168 (and the retaining wall 168 isreceived within the recess 172 defined by the inner walls 170 a and 170b). At this stage, the retaining wall 168 inhibits the inner walls 170 aand 170 b from flexing or deflecting inwardly, thereby maintaining thelatch 166 in a closed or latched configuration and maintaining the innerwalls 170 a and 170 b coupled together.

The retaining wall 168 only extends (e.g., along the longitudinal axis Lof the apparatus 100) a relatively short distance forward from a rearwall 169 of the housing 102. Thus, as the shuttle 125 and the indicator126 continue to travel in the housing 102, the inner walls 170 a and 170b of the first indicator portion 126 a and the second indicator portion126 b move beyond the retaining wall 168 to a location where the innerwalls 170 a and 170 b can flex relative to one another. Particularly, inthe illustrated embodiment, at this point, the inner wall 170 b of thesecond indicator portion 126 b is free to flex inwardly, i.e., relativeto the inner wall 170 a of the first indicator portion 126 a. The thirdstored energy device 146 can now provide (or assist in providing) theenergy necessary to overcome the latch or detent 166 to allow the firstand second indicator portions 126 a and 126 b to become separated, asshown in FIG. 16. The third stored energy device 146 is positioned toengage at least a portion of the second indicator portion 126 b to causethe second indicator portion 126 b to move in a direction opposite theshuttle 125 and the first indicator portion 126 a, e.g., rearwardly inthe housing 102 toward the rear wall 169, with the inner wall 170 briding along and receiving the retaining wall 168.

In some embodiments, at least a portion of the indicator 126 can be inan abutting relationship with the shuttle 125. For example, as shown inFIG. 13, prior to the shuttle 125 reaching its second position S₂, thesecond indicator portion 126 b can be in abutting relationship with arear end of the first indicator portion 126 a and a rear end of theshuttle 125, i.e., until the first indicator portion 126 a and thesecond indicator portion 126 b are separated.

After the first indicator portion 126 a and the second indicator portion126 b are separated, the second stored energy device 144 and the thirdstored energy device 146 are both positioned to continue to move theshuttle 125 and the first indicator portion 126 a in the housing 102toward the second shuttle position S₂. The second stored energy device144 is positioned to continue pushing the plunger 149, while the thirdstored energy device 146 is positioned to move the first indicatorportion 126 a, which is coupled to the plunger 149 (e.g., via the innerwall 170 a). The plunger 149 is positioned to contact and push thepiston 148 to pressurize the reservoir 111 of the cartridge 110, and afront end (i.e., the openable end 151) of the cartridge 110 ispositioned to contact an inner surface of the shuttle 125 to continue todrive the shuttle 125 to its second position S₂ (as shown in FIGS. 17and 22). In some embodiments, the fluid within the cartridge 110 is notpressurized until this step, i.e., until the apparatus 100 is actuatedand the resulting series of events includes pressurizing the cartridge110. For example, in the illustrated embodiment, the second storedenergy device 144 is responsible for launching the shuttle 125 (and thecartridge 110) toward its second position S₂, and the third storedenergy device 146, which is configured to provide greater forces thanthe second stored energy device 144, completes the movement of theshuttle 125, pressurizes and energizes the cartridge 110, and moves thepiston 148 in the reservoir 111 of the cartridge 110.

The second indicator portion 126 b that is configured to be removablycoupled to the first indicator portion 126 a is described as being aportion of the indicator 126 by way of example only. This element caninstead be described as a portion of the shuttle 125, or as a separateelement altogether that is configured to be removably coupled to atleast one of the indicator 126 and the shuttle 125.

By way of example only, the plunger 149 of the illustrated embodiment iscoupled to or provided by (e.g., integrally formed with) the indicator126, such that the indicator 126 includes (i) an inner portion 185(i.e., positioned to comprise or be coupled to the plunger 149), atleast a portion of which is responsible for engaging and moving thepiston 148 in the cartridge 110; and (ii) an outer portion 187configured to ride along an outer surface or wall 188 of the shuttle 125to be visible through the window 124 to display the progress of theinfusion of the active agent (see FIGS. 13, 16, 17 and 22).Specifically, in the illustrated embodiment, the outer portion 187 ofthe indicator 126 is dimensioned to be received between a retaining wall105 of the housing 102 and the outer surface or wall 188 of the shuttle125. That is, the outer portion 187 of the indicator 126 can bedimensioned to receive at least a portion of the shuttle 125, such thatafter the shuttle 125 has been moved to its second position S₂, theindicator 126 can be movable with respect to the shuttle 125.

Furthermore, in the illustrated embodiment, the plunger 149 includes ordefines an internal recess or chamber 171, and the second stored energydevice 144, e.g., in the case where a spring is employed as the secondstored energy device 144, can be dimensioned to be at least partiallyreceived in the recess 173 defined by the retaining wall 168 and extendat least partially into the internal chamber 171 to drive or bias theplunger 149 away from the rear wall 169 of the housing 102.

Additionally, in the illustrated embodiment, the outer portion 187 ofthe indicator 126 includes a first outer recess or chamber 190 definedbetween an inner surface or wall of the outer portion 187 of theindicator 126 and the outer surface or wall 188 of the shuttle 125, thefirst outer recess 190 opening rearwardly. The first outer recess 190can be dimensioned to receive the third stored energy device 146 (e.g.,when a spring is employed as the third stored energy device 146). Assuch, the third stored energy device 146 can be positioned to drive orbias a forward or front end of the indicator 126 forward in the housing102, away from the rear wall 169 of the housing 102. In someembodiments, as shown, the outer portion 187 of the indicator 126 canfurther include a second outer recess 191 dimensioned to receive atleast a portion of the shuttle 125, the second outer recess 191 openingforwardly.

Furthermore, in some embodiments, as shown, the inner portion 185 of theindicator 126 can also include or define an inner recess or chamber 192dimensioned to receive at least a portion of the cartridge 110.Particularly, the inner recess 192 can receive a closed end of thecartridge 110 (e.g., that includes the piston 148), for example, in apress-fit engagement. As shown, the cartridge 110 can be positioned inthe inner recess 192 such that the piston 148 abuts a forward or frontend of the plunger 149.

As shown in FIG. 17, the combined forces provided by the second storedenergy device 144 and the third stored energy device 146 can completethe movement of the shuttle 125 to its second infusing position S₂ wherethe reservoir 111 of the cartridge 110 is placed into fluidcommunication with the fluid path 123. By way of example, as describedabove, the fluid path 123 can include or be coupled to the piercingelement 175 (e.g., a hollow needle) that, by way of example only, canremain fixed with respect to the housing 102 and the shuttle 125. By wayof further example, the cartridge 110 can be fitted with a cap 176 and aseptum 177 that is accessible via the cap 176. In some embodiments, thecartridge 110 can include a glass cylinder, and the open, or openable,end 151 can be closed and sealed by the cap 176. The cap 176 can includea metallic cap, such as an aluminum cap, that can be crimped to the openend 151 of the cartridge 110 in a know manner. The cap 176 can hold theseptum 177 that sealingly closes the otherwise open end 151 of thecartridge 110.

The septum 177 may be made of many different materials including thosetypically used with reservoirs (e.g., drug cartridges). The septum 177may be made of a pierceable and resealable elastomeric seal or septumthat is securely mounted, with or without being crimped, across the openend 151 of the cartridge 110. In some embodiments, the septum 177 (e.g.,formed of an elastomer) may be crimped onto an end of the cartridge 110with a malleable cap 176, e.g., formed of aluminum. Other similar septummaterials and modes of securing it to the open end 151 of the cartridge110 may be used. For example, a septum molded into the body of acylinder may be used, such as the CZ series available from WestPharmaceutical Services, Inc, Lionville, Pa., a cap, such as a standardsyringe luer cap, or a molded end thin enough to be pierced. Suitablematerials are subject to piercing with sufficient piercing force andmaintain a seal once pierced. As noted above, the septum 177 can bepierced during use and seal around the piercing element 175 with enoughforce to prevent leakage during pressurization and transfer of theactive agent from the reservoir 111. Certain septum materials allow theseptum 177 to reseal following withdrawal of the piercing element 175after use. The present disclosure envisions unsealing or opening theotherwise closed septum 177 by a variety of approaches.

When the shuttle 125 is moved to its second position S₂, the piercingelement 175 can pierce or puncture the septum 177, thereby placing thefluid path 123 (i.e., via the interior of the piercing element 175) influid communication with the reservoir 111 of the cartridge 110, asshown in FIG. 17. At this point, as further shown in FIG. 17, the openend 151 of the cartridge 110 (e.g., and the cap 176) abuts a base 178 ofthe piercing element 175, which defines the second position S₂ of theshuttle 125. As a result, the shuttle 125 and the cartridge 110 come toa stop within the housing 102. The third stored energy device 146, anend of which is positioned to engage an end of the indicator 126 can nowtransfer its remaining stored energy to moving the indicator 126 (i.e.,the first indicator portion 126 a), along with the plunger 149, to drivethe piston 148 within the reservoir 111 and force the active agent intothe fluid path 123, via the piercing element 175, to the hollowmicroneedles 108. FIG. 18 shows the indicator 126 beginning to bedisplayed through the window 124 of the housing 102 as the infusionprocess begins. The indicator 126 can be colored or otherwiseconspicuous relative to the other components of the apparatus 100 to beclearly visible to a user.

In the illustrated embodiment, the first side 121 of the holder 106 andthe second side 118 of the microneedle array 107 can be configured to bespaced a distance apart when the microneedle array 107 is coupled to theholder 106 to define a reservoir or manifold 180 therebetween (see FIGS.14, 15, 17 and 22). Particularly, when the microneedle array 107 iscoupled to the holder 106, the second side 118 of the microneedle array107, or a portion thereof, can be spaced a distance from the first side(or base) 121 of the holder 106 to define the reservoir 180. As shown inFIGS. 14 and 15, the reservoir 180 can be configured to be closed on allsides to inhibit leakage. Additional sealing members can be employed asnecessary. The fluid path 123 can include or be in fluid communicationwith the reservoir 180, and the reservoir 180 can be in fluidcommunication with the hollow microneedles 108 (i.e., via the secondside 118 of the microneedle array 107). That is, in some embodiments,the substrate 109 can include one or more channels positioned to extendthereacross to provide fluid communication between the first side 116and the second side 118 of the microneedle array 107. As a result, asthe active agent is driven out of the reservoir 111 of the cartridge 110and into the fluid path 123, the active agent is moved to the reservoir180 that is positioned to deliver or feed the active agent to theplurality of hollow microneedles 108, to in turn deliver the activeagent to the skin 50 via the microneedles 108. Other configurations ofproviding fluid communication between the piercing element 175 (e.g.,the rest of the fluid path 123) and the microneedles 108 are possible,and the reservoir 180 is shown by way of example only.

FIGS. 7, 9, 11, 13, 16, 17, and 19-21 illustrate a sterility seal 182positioned to enclose and maintain the sterility of the piercing element175 prior to piercing the septum 177 and positioning the piercingelement 175 in fluid communication with the reservoir 111 of thecartridge 110. Particularly, FIGS. 19-21 show close-up sidecross-sectional views of the piercing element 175 and the sterility seal182, and particularly, show close-up views of the piercing element 175and the sterility seal 182 of FIGS. 9, 11 and 17, respectively, beforethe seal 182 is punctured, as the seal 182 is punctured, and after theseal 182 is punctured and collapsed.

As the shuttle 125 moves the cartridge 110 to the second position S₂,the septum 177 that is positioned over the open end 151 of the cartridge110 contacts and deforms the seal 182 until the piercing element 175pierces or punctures the seal 182 (see FIG. 20). As the shuttle 125 (andthe cartridge 110) continues moving, the piercing element 175 continuesmoving through the seal 182 as it punctures the septum 177. That is, theseal 182 can be configured to deform and collapse toward the base 178 ofthe piercing element 175, and can be further configured to remain in acollapsed configuration after being pierced (e.g., incapable ofreturning to its original position or configuration), as shown in FIG.21.

In some embodiments, the seal 182 can be formed of materials similarthose described above with respect to the septum 177 that allow the seal182 to be pierced during use and seal around the piercing element 175with enough force to prevent leakage during pressurization and transferof the active agent from the reservoir 111, or at least until thepiercing element 175 pierces the septum 177 and the septum 177 canprevent leakage. In some embodiments, the seal 182 merely collapsesaround the piercing element 175 and does not seal around the piercingelement 175.

As further shown in FIGS. 19-21, the sterility seal 182 can beconfigured to change from a first state (see FIG. 19) in which thesterility seal 182 defines a chamber (e.g., a sterile chamber) 184configured to house the piercing element 175 to a second state (see FIG.21) in which the sterility seal 182 has been pierced by the piercingelement 175 and is collapsed, particularly, between the septum 177 (orthe cap 176 or the open end 151 of the cartridge 110) and the base 178of the piercing element 175. FIG. 20 illustrates a third state orcondition that is intermediate of that shown in FIGS. 19 and 21, inwhich the seal 182 is punctured by the piercing element 175.

As mentioned above, the piston 148 and the plunger 149 can be movabletogether between a first, non-dispensing, position (e.g., as shown inFIG. 17) and a second, dispensed, position (e.g., as shown in FIG. 22),respectively. FIGS. 22 and 23 illustrate the apparatus 100 with thepiston 148 and the plunger 149 in their respective second positions.That is, after fluid communication is established (see FIG. 17) betweenthe fluid path 123 and the reservoir 111 of the cartridge 110, theshuttle 125 is maintained in its second position S₂, and the thirdstored energy device 146 continues to drive the indicator 126 in thehousing 102, e.g., along the longitudinal axis L, which also drives theplunger 149, which in turns moves the piston 148 within the cartridge110 to force the active agent into the fluid path 123. FIG. 23illustrates what a user would see when infusion or delivery of theactive agent is complete and the apparatus 100 can be removed from theskin 50.

In use, the cover 113 and release liner 152 can be removed. Theskin-contact adhesive 150 on the base 133 of the actuator 104 (and/or onthe base 112 of the housing 102) can be applied to the skin 50. An upperportion (e.g., the first portion 120) of the housing 102 of theapparatus 100 can be pressed toward the skin 50 to cause the actuator104 to move from its first position P₁ (as shown in FIGS. 7 and 8, whichillustrate a first condition of the apparatus 100) to its secondposition P₂ (as shown in FIGS. 9 and 10, which illustrate a secondcondition of the apparatus 100), e.g., against the bias of the biasingelement 128.

Movement of the actuator 104 to its second position P₂ releases theshuttle 125 (i.e., by moving the shuttle stop 154) to allow the shuttle125 to begin moving toward its second position S₂ (as shown in FIGS. 11and 12, which illustrate a third condition of the apparatus 100), e.g.,as a result of being driven by the second stored energy device 144 (asshown in FIG. 11). After the shuttle 125 is moved to a third position S₃located between its first and second positions S₁ and S₂, the holderstop 160 on the shuttle 125 is no longer positioned to retain themicroneedle array holder 106 in its retracted position H₁, such that theholder 106 is released, and the first stored energy device 138 can beginto provide forces to drive the microneedle array holder 106 toward itsextended position H₂ (as shown in FIGS. 13-14, which illustrate a fourthcondition of the apparatus 100). In the illustrated embodiment, FIGS. 13and 14 show a dampened position of the holder 106, and the holder 106can continue to its full extended position H₂ (and accordingly, themicroneedle array 107 can continue to its extended position M₂), asshown in FIGS. 15 and 16, which illustrate a fifth condition of theapparatus 100. However, some embodiments do not employ the dampener 163or the dampened position of the holder 106 illustrated in FIGS. 13 and14. The shuttle 125 then continues to move toward its second position S₂and the first indicator portion 126 a and the second indicator portion126 b are allowed to separate (as shown in FIG. 16), at which point thethird stored energy device 146 can provide, or assist in providing,forces to continue to move the shuttle 125 to the second position S₂.

When the shuttle 125 reaches its second position S₂ (as shown in FIG.17, which illustrates a sixth condition of the apparatus 100), thereservoir 111 of the cartridge 110 of the infusion assembly 103 isplaced into fluid communication with the fluid path 123, andparticularly with the microneedles 108 in the injection assembly 101.Also, at this point, the indicator 126 (e.g., the first indicatorportion 126 a) can begin to move relative to the shuttle 125, which candrive the piston 148 in the reservoir 111 (e.g., with the plunger 149),and the progress of the piston 148 can be displayed to a user by theindicator 126, which can be visible through the window 124 in thehousing 102 (as shown in FIG. 18). When the piston 148 and the plunger149 (and the indicator 126) reach their respective second positions (asshown in FIGS. 22 and 23, which illustrate a seventh condition of theapparatus 100), infusion of the active agent is complete. This can beindicated to a user with the indicator 126, which can be visible throughthe window 124 of the housing 102, e.g., by showing the indicator 126 asfilling up the window 124.

FIGS. 24 and 25 illustrate the cover 113 in greater detail. As mentionedabove, the cover 113 can include (i) a first (e.g., outer) portion 140configured to cover at least a portion of the base 112 of the housing102 adjacent the opening 115, as well as the base 133 of the actuator104; and (ii) a second (e.g., inner) portion 142 configured to bereceived in the cavity 114 of the housing 112 and further configured tocover the plurality of microneedles 108 on the microneedle array 107when the microneedle array holder 106 is in the retracted position H₁.The second portion 142 can also be configured to be received in thecavity 134 of the actuator 104, e.g., in embodiments employing anactuator 104 through which the microneedle array 107 is deployed. Inaddition, the first portion 140 can cover the base 133 of the actuator104 adjacent the opening 135 in embodiments employing an actuator 104through which the microneedle array 107 is deployed.

As mentioned above, the base 133 of the actuator 104 and/or the base 112of the housing 102 can include the skin-contact adhesive 150 and anyoptional release liners 152. In such embodiments, the cover 113 (i.e.,the first portion 140 thereof) can be configured to cover at least theportion of the base 133 (and/or the base 112) including the skin-contactadhesive 150 and, optionally, any release liners 152 employed,particularly when the actuator 104 is in the first position P₁. However,in some embodiments, after the apparatus 100 has been used and removedfrom the skin 50, the cover 113 can be used to re-cover the actuator 104and the base 112 of the housing 102, with the actuator 104 in its secondposition P₂.

In the illustrated embodiment, the first portion 140 and the secondportion 142 of the cover 113 are integrally formed together. However, insome embodiments, the first and second portions 140 and 142 can beremovably coupled together (e.g., by any of the removable coupling meansdescribed above), which can allow the base 133 (and/or the base 112) tobe covered and/or uncovered independently of the microneedles 108.

By way of example only, the second portion 142 is illustrated as beinggenerally tubular in shape, such that the second portion 142 can extendthrough the opening 135 (and/or the opening 115) in the base 133 (and/orthe base 112) and into the cavity 134 of the actuator 104 (and/or thecavity 114 of the housing 112).

As shown in FIG. 25, the first portion 140 can include or define arecess (or chamber or pocket) 195 (i.e., with a closed end 197)dimensioned to receive at least a portion of the base 133 of theactuator 104 and/or at least a portion of the base 112 of the housing102. In embodiments in which the cover 113 covers the actuator 104, theclosed end or base 197 of the recess 195 can be spaced a distance fromthe base 133 of the actuator 104 when the cover 113 is coupled to theapparatus 100, such that the actuator 104 is not undesirably orprematurely actuated 104 prior to use.

As further shown, the second portion 142 can include or define a recess(or chamber or pocket) 196 (i.e., with a closed end 198) dimensioned toreceive the plurality of microneedles 108 protruding from the firstmajor surface of the first side 116 of the microneedle array 107. Therecess 196 (e.g., the closed end 198) in the second portion 142 can beat least partially defined by an inner surface, and the inner surface ofthe recess 196 and the first side 116 of the microneedle array 107 cantogether define a sterile chamber for housing the plurality ofmicroneedles 108 after assembly of the apparatus 100 and prior to use.Such a sterile chamber can allow sterilizing agent(s) free access to theenclosed volume, while keeping contaminants from entering the chamberpost-sterilization.

As further shown in FIG. 25, in some embodiments, the second portion 142of the cover 113 can include at least one of a projection and a recess,and the first side 116 of the microneedle array 107 (and/or the firstside 121 of the holder 106) can include at least one of a recess and aprojection, respectively, dimensioned to receive the projection and/orproject into the recess of the second portion 142 of the cover 113. Suchan arrangement can allow the second portion 142 to matingly engage withthe microneedle array 107 (and/or the holder 106) and to facilitatehousing and protecting the microneedle array 107 with the second portion142 of the cover 113.

As shown in FIGS. 3 and 25, in the illustrated embodiment, amicroneedle-facing (e.g., an upwardly-facing) recess 199 is illustratedin the second portion 142 of the cover 113 by way of example. As shown,the first side 116 of the microneedle array 107 can include acover-facing (e.g., a downwardly-facing) recess 139 that surrounds theplurality of microneedles 108. As shown in FIGS. 3, 4 and 6, a sealingmember 136 can be employed that is dimensioned to be received in therecess 199 in the second portion 142 of the cover 113 and the recess 139in the microneedle array 107 to seal or close the chamber configured tohouse the microneedles 108 and to provide additional spacing between theclosed end 198 of the recess 196 of the second portion 142 of the cover113 and the first side 116 of the microneedle array 107. This specificarrangement is shown by way of example only, but generally, the secondportion 142 of the cover 113 can be configured to be coupled in some wayto the first side 116 of the microneedle array 107 (and/or the holder106) to enclose and protect the plurality of microneedles 108 prior touse, i.e., to maintain the sterility of the microneedles 108 In someembodiments, the sealing member 136 and/or a portion of the cover 113can be permeable to sterilizing agent(s)) while inhibiting contaminantsfrom entering the chamber after sterilization. In some embodiments, thesecond portion 142 can include or provide the sealing member 136. Insuch embodiments, the sealing member 136 may be integrally formed withthe cover 113 and configured to be coupled to at least one of the firstside 116 of the microneedle array 107 and the first side 121 of themicroneedle array holder 106.

As mentioned above, the housing 102 can include a protrusion 119 thatdefines or includes the base 112. The actuator 104 (e.g., the outerportion 132 thereof) can extend outwardly (e.g., downwardly) from theprotrusion, e.g., when the actuator 104 is in its first position P₁. Therecess 195 in the first portion 140 of the cover 113 can be dimensionedto receive the protrusion of the housing 119 and/or at least a portionof the outer portion 132 of the actuator 104.

The cover 113 can be configured to be coupled to the housing 102 (e.g.,the protrusion 119) and/or the actuator 104 by any of the coupling meansdescribed above. The cover 113 can also be configured to abut a portionof the housing 102 from which the protrusion 119 projects, which canfacilitate inhibiting the cover 113 from pressing the actuator 104 whenthe cover 113 is coupled to the apparatus 100 to prevent prematureactuation of the actuator 104.

While the embodiment of FIGS. 1-25 employs a specific configuration andarrangement of elements and stored energy devices to accomplishinjection and, optionally, infusion, it should be understood thatvariations to the specific structures and arrangements shown in theillustrated embodiment are within the spirit and scope of the presentdisclosure.

For example, FIG. 26 illustrates an apparatus 100′ according to anotherembodiment of the present disclosure, and particularly, a portion of aninfusion assembly 103′ according to another embodiment of the presentdisclosure. In some embodiments, as shown in FIG. 26, the third storedenergy device 146′ can be configured to directly (rather thanindirectly) engage the plunger 149′ and/or the piston 148′, and theindicator 126′ (e.g., the outer portion 187′ thereof) can still includean outer recess 190′ configured to receive at least a portion of theshuttle 125′ and can ride along the outer surface of the shuttle 125′between the shuttle 125′ and one or more retaining walls 105′ of thehousing 102′ in order to be visible through a window of the housing 102′to indicate the progression of infusion.

For example, in such embodiments, the third stored energy device 146′can be located within the internal chamber 171′ of the inner portion185′ of the indicator 126′ that defines the plunger 149′ (i.e., asopposed to being located between an outer surface of the shuttle 125 andthe outer portion 187′ of the indicator 126). A front end or wall of theplunger 149′ can still contact the piston 148′. Furthermore, in suchembodiments, the second stored energy device 144′ can still initiate themovement of the shuttle 125′ as well as the decoupling of first andsecond indicator portions 125 a′ and 125 b′. Similar to the apparatus100 of FIGS. 1-25, in the apparatus 100′, the first indicator portion126 a′ is located between the shuttle 125′ and the second indicatorportion 126 b′ (and provides coupling therebetween). Still further, theindicator 126′ (or a portion thereof, particularly, the first indicatorportion 126 a′) can travel with the shuttle 125′ until the shuttle 125′reaches its second position, after which, the outer portion 187′ canreach a longitudinal location along longitudinal axis L′ that is beyonda retaining wall 193, allowing the walls forming the outer portion 187′of the indicator 126′ to flex outwardly. At that point, the third storedenergy device 146′ can provide forces to overcome a latch or detent 194coupling the indicator 126′ (i.e., the first indicator portion 126 a′)and the shuttle 125′, allowing the indicator 126′ to begin to move alongthe longitudinal axis L′, relative to the shuttle 125′, allowing theshuttle 125′ to ride inside the outer portion 187′ (i.e., in the outerrecess 190′) to drive the piston 148′ in the cartridge 110′ to infuse anactive agent.

Each embodiment shown in the figures is illustrated as a separateembodiment for clarity in illustrating a variety of features of theapparatuses of the present disclosure. However, it should be understoodthat any combination of elements and features of any of the embodimentsillustrated in the figures and described herein can be employed in theapparatuses of the present disclosure.

The following descriptions of the application time, microneedles,skin-contact adhesive, release liners, and active agents can apply toany embodiment of the apparatuses of the present disclosure.

In some embodiments, the length of time that apparatuses of the presentdisclosure can remain on the skin 50 may be an extended time, however,apparatuses of the present disclosure are more likely to remain on theskin 50 for shorter durations of time. For example, in some embodiments,apparatuses of the present disclosure can remain on the skin for atreatment period of at least 1 second, in some embodiments, at least 5seconds, in some embodiments, at least 10 seconds, in some embodiments,at least 15 seconds, and in some embodiments, at least 30 seconds. Insome embodiments, the apparatus can remain on the skin for a period oftime of no greater than 1 hour, in some embodiments, no greater than 30minutes, in some embodiments, no greater than 20 minutes, in someembodiments, no greater than 10 minutes, and in some embodiments, nogreater than 5 minutes. In some embodiments, the apparatuses can remainon the skin for a treatment period of from 1 second to 1 hour, in someembodiments, from 10 seconds to 10 minutes, and in some embodiments,from 30 seconds to 5 minutes.

In some embodiments, the apparatus 100 can be configured to deliver anactive agent over an infusion period of at least 1 second, in someembodiments, at least 5 seconds, in some embodiments, at least 10seconds, in some embodiments, at least 15 seconds, and in someembodiments, at least 30 seconds. In some embodiments, apparatuses ofthe present disclosure can include infusion periods of no greater thanno greater than 1 hour, in some embodiments, no greater than 30 minutes,in some embodiments, no greater than 20 minutes, in some embodiments, nogreater than 10 minutes, and in some embodiments, no greater than 5minutes. In some embodiments, the apparatuses can remain on the skin fora treatment period of from 1 second to 1 hour, in some embodiments, from10 seconds to 10 minutes, and in some embodiments, from 30 seconds to 5minutes.

Skin-Contact Adhesive

In some embodiments, the skin-contact adhesive 150 can cover the entirebase 133 of the actuator 104 (and/or the base 112 of the housing 102).Alternatively, in some embodiments, the skin-contact adhesive 150 canpartially cover the base 133 (and/or the base 112), e.g., includingintermittent application of the skin-contact adhesive 150 to create gaps(e.g., randomly, or in a pattern), and/or a complete ring ofskin-contact adhesive 150 that has a width that is less than the widthof the base 133 (and/or the base 112).

The skin-contact adhesive 150 is generally a pressure-sensitiveadhesive, and particularly is a pressure-sensitive adhesive that iscapable of securely but releasably adhering or bonding to skin (e.g.,mammalian skin). The skin-contact adhesive 150 is also generally safeand non-toxic. Skin-contact adhesive layers will generally be selectedaccording to the desired end use of the apparatus 100. In someembodiments, the apparatus 100 can include more than one skin-contactadhesive 150. Where the apparatus 100 comprises more than oneskin-contact adhesive layer 150, each skin-contact adhesive layer 150may be selected independently of each other with regard to material andthickness used. Examples of suitable adhesives include acrylates,silicones, polyisobutylenes, synthetic rubber, natural rubber, andcopolymers and mixtures thereof. Acrylates and silicones can bepreferred skin-contact adhesives 150. In general, the skin-contactadhesive 150 should cause little or no irritation or sensitization ofthe skin during the intended wear period.

In some embodiments, the skin-contact adhesive 150 can be an acrylate(or methacrylate) copolymer. Acrylates will typically have an inherentviscosity greater than about 0.2 dL/g and will comprise one or morepolymerized primary monomers and optionally one or more polarcomonomers. Primary monomers suitable for use include alkyl acrylatescontaining 4 to 12 carbon atoms in the alkyl group and alkylmethacrylates containing 4 to 12 carbon atoms in the alkyl group.Examples of suitable alkyl acrylates and methacrylates include n-butyl,n-pentyl, n-hexyl, isoheptyl, n-nonyl, n-decyl, isohexyl, 2-ethyloctyl,isooctyl and 2-ethylhexyl acrylates and methacrylates. In someembodiments, the alkyl acrylates can include isooctyl acrylate,2-ethylhexyl acrylate, n-butyl acrylate, and cyclohexyl acrylate. Polarmonomers suitable for use can include those having hydroxyl, amide, orcarboxylic, sulfonic, or phosphonic acid functionality. Representativeexamples include acrylamide, methacrylamide, N-vinyl-2-pyrrolidone,2-hydroxyethylacrylate, 2-hydroxyethylmethacrylate,hydroxypropylacrylate, acrylic acid, methacrylic acid, pyrrolidonylethyl acrylate, and alkoxyethyl acrylates, such as2-carboxyethylacrylate. In some embodiments, the amount by weight ofpolar monomer will not exceed about 40% of the total weight of allmonomers in order to avoid excessive firmness of the final PSA product.Typically, polar monomers can be incorporated to the extent of about 1%to about 20% by weight. In some embodiments, the polar monomer can beacrylamide.

In some embodiments, the acrylate copolymer can comprise the reactionproduct of primary and polar monomers and additional optional monomerswhich, when present, are included in the polymerization reaction inquantities that will not render the adhesive composition non-tacky. Theoptional additional monomers may be added, for example, to improveperformance, reduce cost, or for other purposes. Examples of suchoptional monomers include vinyl esters, such as vinyl acetate, vinylchloride, vinylidene chloride, styrene, and macromonomerscopolymerizable with the other monomers. Suitable macromonomers includepolymethylmethacrylate, styrene/acrylonitrile copolymer, polyether, andpolystyrene macromonomers. Examples of useful macromonomers and theirpreparation are described in U.S. Pat. No. 4,693,776 (Krampe et al.),the disclosure of which is incorporated herein by reference.

Silicone or polysiloxane pressure-sensitive adhesives includepressure-sensitive adhesives which are based on two major components: apolymer, or gum, and a tackifying resin. The polysiloxane adhesive canbe prepared by cross-linking the gum, typically a high molecular weightpolydiorganosiloxane, with the resin, to produce a three-dimensionalsilicate structure, via a condensation reaction in an appropriateorganic solvent. The ratio of resin to polymer can be adjusted in orderto modify the physical properties of polysiloxane adhesives. Use ofcapped (or amine-compatible) polysiloxanes can, in some embodiments, bepreferred so as to increase drug stability and reduce degradation.Further details and examples of silicone pressure-sensitive adhesiveswhich can be useful are described in the U.S. Pat. No. 4,591,622(Blizzard et al.); U.S. Pat. No. 4,584,355 (Blizzard et al.); U.S. Pat.No. 4,585,836 (Homan et al.); and U.S. Pat. No. 4,655,767 (Woodard etal.). Suitable silicone pressure-sensitive adhesives are commerciallyavailable and include the silicone adhesives sold under the trademarksBIO-PSA® by Dow Corning Corporation, Medical Products, Midland, Mich.

Further description of suitable adhesives may be found in U.S. Pat. No.5,656,286 (Miranda et al.), U.S. Pat. No. 5,223,261 (Nelson et al.), andU.S. Pat. No. 5,380,760 (Wendel et al.), the disclosures of which areincorporated herein by reference. In some embodiments, the thickness ofthe skin-contact adhesive 150 can be at least about 10 μm, in someembodiments, at least about 20 μm, and in some embodiments, at leastabout 40 μm. In some embodiments, the thickness of the skin-contactadhesive 150 can be less than about 2 mm (0.07874 inch), in someembodiments, less than about 1 mm (0.03937 inch), and in someembodiments, less than about 150 microns (5906 microinches).

In some embodiments, a medical grade adhesive can be preferred for theskin-contact adhesive 150. Such a medical grade skin-contact adhesive150 is can have physical properties and characteristics to be capable ofmaintaining intimate contact with the skin 50 before, during, and afteractuation of the apparatus 100. Securing the actuator 104 (or thehousing 102) to the skin 50 can aid in keeping the microneedles 108inserted into the skin 50.

Release Liners

Release liners, which can be used as at least a portion the releaseliner 152 (in addition to other release liners that are employed, e.g.,to cover at least a portion of the base 112), are available from avariety of manufacturers in a wide variety of proprietary formulations.Those skilled in the art will normally test those liners in simulateduse conditions against an adhesive of choice to arrive at a product withthe desired release characteristics. Liners which can be suitable foruse in apparatuses of the present disclosure can be made of kraftpapers, polyethylene, polypropylene, polyester or composites of any ofthese materials. The liner material can be coated with release agents orlow adhesion coatings, such as fluorochemicals or silicones. Forexample, U.S. Pat. No. 4,472,480 (Olson), the disclosure of which ishereby incorporated by reference, describes low surface energyperfluorochemical liners. The liners can be papers, polyolefin films, orpolyester films coated with silicone release materials. Examples ofcommercially available silicone coated release papers are POLYSLIK®silicone release papers available from Loparex (Willowbrook, Ill.).

Active Agent

As mentioned above, in some embodiments, active ingredients or agents(e.g., drugs) can be delivered via the microneedles 108 (e.g., via solidor hollow microneedles). Any substance that can be formulated in a fluidand delivered via hypodermic injection may be used as the active agent,including any pharmaceutical, nutraceutical, cosmeceutical, diagnostic,and therapeutic agents (collectively referred to herein as “drug” forconvenience). The present description envisions that even a gaseousfluid may be utilized.

Examples of drugs that can be incorporated into the apparatuses of thepresent disclosure are those capable of local or systemic effect whenadministered to the skin. Some examples include buprenorphine,clonidine, diclofenac, estradiol, granisetron, isosorbide dinitrate,levonorgestrel, lidocaine, methylphenidate, nicotine, nitroglycerine,oxybutynin, rivastigmine, rotigotine, scopolamine, selegiline,testosterone, tulobuterol, and fentanyl, which are commerciallyavailable in the form of transdermal devices. Other examples includeantiinflammatory drugs, both steroidal (e.g., hydrocortisone,prednisolone, triamcinolone) and nonsteroidal (e.g., naproxen,piroxicam); bacteriostatic agents (e.g., chlorhexidine,hexylresorcinol); antibacterials (e.g., penicillins such as penicillinV, cephalosporins such as cephalexin, erythromycin, tetracycline,gentamycin, sulfathiazole, nitrofurantoin, and quinolones such asnorfloxacin, flumequine, and ibafloxacin); antiprotazoals (e.g.,metronidazole); antifungals (e.g., nystatin); coronary vasodilators;calcium channel blockers (e.g., nifedipine, diltiazem); bronchodilators(e.g., theophylline, pirbuterol, salmeterol, isoproterenol); enzymeinhibitors such as collagenase inhibitors, protease inhibitors,acetylcholinesterase inhibitors (e.g., donepezil), elastase inhibitors,lipoxygenase inhibitors (e.g., A64077), and angiotensin convertingenzyme inhibitors (e.g., captopril, lisinopril); other antihypertensives(e.g., propranolol); leukotriene antagonists (e.g., ICI204,219);anti-ulceratives such as H2 antagonists; steroidal hormones (e.g.,progesterone); antivirals and/or immunomodulators (e.g.,1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine,1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine,N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide,and acyclovir); local anesthetics (e.g., benzocaine, propofol,tetracaine, prilocaine); cardiotonics (e.g., digitalis, digoxin);antitussives (e.g., codeine, dextromethorphan); antihistamines (e.g.,diphenhydramine, chlorpheniramine, terfenadine); narcotic analgesics(e.g., morphine, fentanyl citrate, sufentanil, hydromorphonehydrochloride); peptide hormones (e.g., human or animal growth hormones,LHRH, parathyroid hormones); cardioactive products such asatriopeptides; antidiabetic agents (e.g., insulin, exanatide); enzymes(e.g., anti-plaque enzymes, lysozyme, dextranase); antinauseants;anticonvulsants (e.g., carbamazine); immunosuppressives (e.g.,cyclosporine); psychotherapeutics (e.g., diazepam); sedatives (e.g.,phenobarbital); anticoagulants (e.g., heparin, enoxaparin sodium);analgesics (e.g., acetaminophen); antimigraine agents (e.g., ergotamine,melatonin, sumatriptan, zolmitriptan); antiarrhythmic agents (e.g.,flecainide); antiemetics (e.g., metaclopromide, ondansetron, granisetronhydrochloride); anticancer agents (e.g., methotrexate); neurologicagents such as anxiolytic drugs; hemostatics; anti-obesity agents;dopamine agonists (e.g., apomorphine); GnRH agonists (e.g., leuprolide,goserelin, nafarelin); fertility hormones (e.g., hCG, hMG,urofollitropin); interferons (e.g., interferon-alpha, interferon-beta,interferon-gamma, pegylated interferon-alpha); and the like, as well aspharmaceutically acceptable salts and esters thereof. The amount of drugthat constitutes a therapeutically effective amount can be readilydetermined by those skilled in the art with due consideration of theparticular drug, the particular carrier, and the desired therapeuticeffect.

In some embodiments, peptide therapeutic agents (natural, synthetic, orrecombinant) can be delivered via the microneedles 108 (e.g., via solidor hollow microneedles). Examples of peptide therapeutic agents that canbe incorporated into the apparatuses of the present disclosure includeparathyroid hormone (PTH), parathyroid hormone related protein (PTHrP),calcitonin, lysozyme, insulin, insulinotropic analogs, glatirameracetate, goserelin acetate, somatostatin, octreotide, leuprolide,vasopressin, desmopressin, thymosin alpha-1, atrial natriuretic peptide(ANP), endorphin, vascular endothelial growth factor (VEGF),fibroblast-growth factor (FGF), erythropoietin (EPO), bone morphogeneticproteins (BMPs), epidermal growth factor (EFG), granulocytecolony-stimulating factor (G-CSF), granulocyte macrophage colonystimulating factor (GM-CSF), insulin-like growth factor (IGF),platelet-derived growth factor (PDGF), growth hormone release hormone(GHRH), dornase alfa, tissue plasminogen activator (tPA), urokinase, ANPclearance inhibitors, luteinizing hormone releasing hormone (LHRH),melanocyte stimulating hormones (alpha & beta MSH), pituitary hormones(hGH), adrenocorticotropic hormone (ACTH), human chorionic gonadotropin(hCG), streptokinase, interleukins (e.g. IL-2, IL-4, IL-10, IL-12,IL-15, IL-18), protein C, protein S, angiotensin, angiogenin,endothelins, pentigetide, brain natriuretic peptide (BNP), neuropeptideY, islet amyloid polypeptide (IAPP), vasoactive intestinal peptide(VIP), hirudin, glucagon, oxytocin, and derivatives of any of theforegoing peptide therapeutic agents.

In some embodiments, drugs that are of a large molecular weight may bedelivered transdermally. Increasing molecular weight of a drug typicallycan cause a decrease in unassisted transdermal delivery. Examples ofsuch large molecules include proteins, peptides, nucleotide sequences,monoclonal antibodies, vaccines, polysaccharides, such as heparin, andantibiotics, such as ceftriaxone. Examples of suitable vaccines includetherapeutic cancer vaccines, anthrax vaccine, flu vaccine, Lyme diseasevaccine, rabies vaccine, measles vaccine, mumps vaccine, chicken poxvaccine, small pox vaccine, hepatitis vaccine, hepatitis A vaccine,hepatitis B vaccine, hepatitis C vaccine, pertussis vaccine, rubellavaccine, diphtheria vaccine, encephalitis vaccine, Japanese encephalitisvaccine, respiratory syncytial virus vaccine, yellow fever vaccine,recombinant protein vaccine, DNA vaccines, polio vaccine, therapeuticcancer vaccine, herpes vaccine, human papilloma virus vaccine,pneumococcal vaccine, meningitis vaccine, whooping cough vaccine,tetanus vaccine, typhoid fever vaccine, cholera vaccine, tuberculosisvaccine, severe acute respiratory syndrome (SARS) vaccine, HSV-1vaccine, HSV-2 vaccine, HIV vaccine and combinations thereof. The term“vaccine” thus includes, without limitation, antigens in the forms ofproteins, polysaccharides, oligosaccharides, or weakened or killedviruses. Additional examples of suitable vaccines and vaccine adjuvantsare described in U.S. Publication No. 2004/0049150 (Dalton et al.), thedisclosure of which is hereby incorporated by reference.

In another embodiment, small-molecule drugs that are otherwise difficultor impossible to deliver by passive transdermal delivery may be used.Examples of such molecules include salt forms; ionic molecules, such asbisphosphonates, including sodium alendronate or pamedronate; andmolecules with physicochemical properties that are not conducive topassive transdermal delivery.

Microneedles

Microneedle arrays useful for practicing the present disclosure can havea variety of configurations and features, such as those described in thefollowing patents and patent applications, the disclosures of which areincorporated herein by reference. One embodiment for the microneedlearrays includes the structures disclosed in U.S. Patent ApplicationPublication No. 2005/0261631 (Clarke et al.), which describesmicroneedles having a truncated tapered shape and a controlled aspectratio. Another embodiment for the microneedle arrays includes thestructures disclosed in U.S. Pat. No. 6,091,975 (Daddona et al.), whichdescribes blade-like microprotrusions for piercing the skin. Stillanother embodiment for the microneedle arrays includes the structuresdisclosed in U.S. Pat. No. 6,312,612 (Sherman et al.), which describestapered structures having a hollow central channel. Yet still anotherembodiment for the microneedle arrays includes the structures disclosedin U.S. Pat. No. 6,379,324 (Gartstein et al.), which describes hollowmicroneedles having at least one longitudinal blade at the top surfaceof the tip of the microneedle. A further embodiment for the microneedlearrays includes the structures disclosed in U.S. Patent ApplicationPublication Nos. US2012/0123387 (Gonzalez et al.) and US2011/0213335(Burton et al.), which both describe hollow microneedles. A stillfurther embodiment for the microneedle arrays includes the structuresdisclosed in U.S. Pat. No. 6,558,361 (Yeshurun) and U.S. Pat. No.7,648,484 (Yeshurun et al.), which both describe hollow microneedlearrays and methods of manufacturing thereof.

Various embodiments of microneedles that can be employed in themicroneedle arrays of the present disclosure are described in PCTPublication No. WO 2012/074576 (Duan et al.), which describes liquidcrystalline polymer (LCP) microneedles; and PCT Publication No. WO2012/122162 (Zhang et al.), which describes a variety of different typesand compositions of microneedles that can be employed in themicroneedles of the present disclosure.

In some embodiments, the microneedle material can be (or include)silicon, glass, or a metal such as stainless steel, titanium, or nickeltitanium alloy. In some embodiments, the microneedle material can be (orinclude) a polymeric material, such as a medical grade polymericmaterial. Exemplary types of medical grade polymeric materials includepolycarbonate, liquid crystalline polymer (LCP), polyether ether ketone(PEEK), cyclic olefin copolymer (COC), polybutylene terephthalate (PBT).Particularly useful types of medical grade polymeric materials includepolycarbonate and LCP.

In some embodiments, the microneedle material can be (or include) abiodegradable polymeric material, particularly, a medical gradebiodegradable polymeric material. Exemplary types of medical gradebiodegradable materials include polylactic acid (PLA), polyglycolic acid(PGA), PGA and PLA copolymer, polyester-amide polymer (PEA).

In some embodiments, the microneedles can be a prepared from adissolvable, degradable, or disintegradable material referred to hereinas “dissolvable microneedles”. A dissolvable, degradable, ordisintegradable material is any solid material that dissolves, degrades,or disintegrates during use. In particular, a “dissolvable microneedle”dissolves, degrades, or disintegrates sufficiently in the tissueunderlying the stratum corneum to allow a therapeutic agent to bereleased into the tissue. The therapeutic agent may be coated on orincorporated into a dissolvable microneedle. In some embodiments, thedissolvable material is selected from a carbohydrate or a sugar. In someembodiments, the dissolvable material is polyvinyl pyrrolidone (PVP). Insome embodiments, the dissolvable material is selected from the groupconsisting of hyaluronic acid, carboxymethylcellulose,hydroxypropylmethylcellulose, methylcellulose, polyvinyl alcohol,sucrose, glucose, dextran, trehalose, maltodextrin, and a combinationthereof.

In some embodiments, the microneedles can be made from (or include) acombination of two or more of any of the above mentioned materials. Forexample, the tip of a microneedle may be a dissolvable material, whilethe remainder of the microneedle is a medical grade polymeric material.

A microneedle or the plurality of microneedles in a microneedle arrayuseful for practicing the present disclosure can have a variety ofshapes that are capable of piercing the stratum corneum. In someembodiments, one or more of the plurality of microneedles can have asquare pyramidal shape, triangular pyramidal shape, stepped pyramidalshape, conical shape, microblade shape, or the shape of a hypodermicneedle. In some embodiments, one or more of the plurality ofmicroneedles can have a square pyramidal shape. In some embodiments, oneor more of the plurality of microneedles can have a triangular pyramidalshape. In some embodiments, one or more of the plurality of microneedlescan have a stepped pyramidal shape. In some embodiments, one or more ofthe plurality of microneedles can have a conical shape. In someembodiments, one or more of the plurality of microneedles can have amicroblade shape. In some embodiments, one or more of the plurality ofmicroneedles can have the shape of a hypodermic needle. The shape can besymmetric or asymmetric. The shape can be truncated (for example, theplurality of microneedles can have a truncated pyramid shape ortruncated cone shape). In some embodiments, the plurality ofmicroneedles in a microneedle array are solid microneedles (that is, themicroneedles are solid throughout). In some embodiments, the pluralityof solid microneedles in a solid microneedle array can have a squarepyramidal shape, triangular pyramidal shape, stepped pyramidal shape,conical shape, or microblade shape. In a preferred embodiment, theplurality of solid microneedles in a solid microneedle array each have asquare pyramidal shape.

In some embodiments, the plurality of microneedles in a microneedlearray are hollow microneedles (that is, the microneedles contain ahollow bore through the microneedle). The hollow bore can be from thebase of the microneedle to the tip of the microneedle or the bore can befrom the base of the microneedle to a position offset from the tip ofthe microneedle. In some embodiments, one or more of the plurality ofhollow microneedles in a hollow microneedle array can have a conicalshape, cylindrical shape, square pyramidal shape, triangular pyramidalshape, or the shape of a hypodermic needle.

In some embodiments, one or more of the plurality of hollow microneedlesin a hollow microneedle array can have a conical shape. In someembodiments, one or more of the plurality of hollow microneedles in ahollow microneedle array can have a cylindrical shape. In someembodiments, one or more of the plurality of hollow microneedles in ahollow microneedle array can have a square pyramidal shape. In someembodiments, one or more of the plurality of hollow microneedles in ahollow microneedle array can have a triangular pyramidal shape. In someembodiments, one or more of the plurality of hollow microneedles in ahollow microneedle array can have the shape of a hypodermic needle. In apreferred embodiment, the plurality of hollow microneedles in a hollowmicroneedle array each have the shape of a conventional hypodermicneedle.

FIG. 27 shows a portion of the microneedle array 107 that includes fourmicroneedles 108 (of which two are referenced in FIG. 27) positioned ona microneedle substrate 109. Each microneedle 108 has a height h, whichis the length from the tip of the microneedle 108 to the microneedlebase at substrate 109. Either the height of a single microneedle or theaverage height of all microneedles on the microneedle array can bereferred to as the height of the microneedle, h. In some embodiments,each of the plurality of microneedles (or the average of all of theplurality of microneedles) has a height of about 100 to about 3000micrometers, in some embodiments, about 100 to about 1500 micrometers,in some embodiments, about 100 to about 1200 micrometers, and, in someembodiments, about 100 to about 1000 micrometers.

In some embodiments, each of the plurality of microneedles (or theaverage of all of the plurality of microneedles) has a height of about200 to about 1200 micrometers, about 200 to about 1000 micrometers,about 200 to about 750 micrometers, or about 200 to about 600micrometers.

In some embodiments, each of the plurality of microneedles (or theaverage of all of the plurality of microneedles) has a height of about250 to about 1500 micrometers, about 500 to about 1000 micrometers, orabout 500 to about 750 micrometers.

In some embodiments, each of the plurality of microneedles (or theaverage of all of the plurality of microneedles) has a height of about800 to about 1400 micrometers.

In some embodiments, each of the plurality of microneedles (or theaverage of all of the plurality of microneedles) has a height of about500.

In some embodiments, each of the plurality of microneedles (or theaverage of all of the plurality of microneedles) has a height of lessthan about 3000 micrometers. In other embodiments, each of the pluralityof microneedles (or the average of all of the plurality of microneedles)has a height of less than about 1500 micrometers. In still otherembodiments, each of the plurality of microneedles (or the average ofall of the plurality of microneedles) has a height of less than about1200 micrometers. In yet still other embodiments, each of the pluralityof microneedles (or the average of all of the plurality of microneedles)has a height of less than about 1000 micrometers. In furtherembodiments, each of the plurality of microneedles (or the average ofall of the plurality of microneedles) has a height of less than about750 micrometers. In still further embodiments, each of the plurality ofmicroneedles (or the average of all of the plurality of microneedles)has a height of less than about 600 micrometers.

In some embodiments, each of the plurality of microneedles (or theaverage of all of the plurality of microneedles) has a height of atleast about 100 micrometers. In other embodiments, each of the pluralityof microneedles (or the average of all of the plurality of microneedles)has a height of at least about 200 micrometers. In still otherembodiments, each of the plurality of microneedles (or the average ofall of the plurality of microneedles) has a height of at least about 250micrometers. In further embodiments, each of the plurality ofmicroneedles (or the average of all of the plurality of microneedles)has a height of at least about 500 micrometers. In still furtherembodiments, each of the plurality of microneedles (or the average ofall of the plurality of microneedles) has a height of at least about 800micrometers.

In some embodiments employing solid microneedles, each of the pluralityof solid microneedles (or the average of all of the plurality of solidmicroneedles) has a height of about 100 to about 1500 micrometers, about100 to about 1200 micrometers, about 200 to about 1000 micrometers,about 200 to about 750 micrometers, about 200 to about 600 micrometers,or about 500 micrometers.

In some embodiments employing hollow microneedles, each of the pluralityof hollow microneedles (or the average of all of the plurality of hollowmicroneedles) has a height of about 100 to about 3000 micrometers, about800 to about 1400 micrometers, or about 500 micrometers.

In some embodiments, each of the plurality of hollow microneedles (orthe average of all of the plurality of hollow microneedles) has a heightof about 900 to about 1000 micrometers. In other embodiments, each ofthe plurality of hollow microneedles (or the average of all of theplurality of hollow microneedles) has a height of about 900 to about 950micrometers. In still other embodiments, each of the plurality of hollowmicroneedles (or the average of all of the plurality of hollowmicroneedles) has a height of about 900 micrometers.

A single microneedle or the plurality of microneedles in a microneedlearray can also be characterized by their aspect ratio. The aspect ratioof a microneedle is the ratio of the height of the microneedle, h to thewidth (at the base of the microneedle), w (as shown in FIG. 27). Theaspect ratio can be presented as h:w. In some embodiments, each of theplurality of microneedles (or the average of all the plurality ofmicroneedles) has (have) an aspect ratio in the range of 2:1 to 5:1. Insome of these embodiments, each of the plurality of microneedles (or theaverage of all of the plurality of microneedles) has (have) an aspectratio of at least 3:1.

In some embodiments, the array of microneedles contains about 100 toabout 1500 microneedles per cm² of the array of microneedles.

In some embodiments employing solid microneedles, the array of solidmicroneedles contains about 100 to about 1500 solid microneedles per cm²of the array of solid microneedles.

In some embodiments, the array of solid microneedles contains about 200to about 500 solid microneedles per cm² of the array of solidmicroneedles.

In some embodiments, the array of solid microneedles contains about 300to about 400 solid microneedles per cm² of the array of solidmicroneedles.

In some embodiments employing hollow microneedles, the array of hollowmicroneedles contains about 3 to about 30 hollow microneedles per arrayof hollow microneedles.

In some embodiments, the array of hollow microneedles contains about 10to about 30 hollow microneedles per array of hollow microneedles.

In some embodiments, the array of hollow microneedles contains about 3to about 20 hollow microneedles per array of hollow microneedles.

In some embodiments, the array of hollow microneedles contains about 13to about 20 hollow microneedles per array of hollow microneedles.

In some embodiments, the array of hollow microneedles contains about 8to about 18 hollow microneedles per array of hollow microneedles.

In some embodiments, the array of hollow microneedles contains about 18hollow microneedles per array of hollow microneedles.

In some embodiments, the array of hollow microneedles contains about 12hollow microneedles per array of hollow microneedles.

In some embodiments, each of the plurality of microneedles (or theaverage of all of the plurality of microneedles) in a microneedle arraycan penetrate into the skin to a depth of about 50 to about 1500micrometers, about 50 to about 400 micrometers, or about 50 to about 250micrometers.

In some embodiments, each of the plurality of microneedles (or theaverage of all of the plurality of microneedles) in a microneedle arraycan penetrate into the skin to a depth of about 100 to about 400micrometers, or about 100 to about 300 micrometers.

In some embodiments, each of the plurality of microneedles (or theaverage of all of the plurality of microneedles) in a microneedle arraycan penetrate into the skin to a depth of about 150 to about 1500micrometers, or about 800 to about 1500 micrometers.

In some embodiments, each of the plurality of microneedles (or theaverage of all of the plurality of microneedles) in a microneedle arraycan penetrate into the skin to a depth of about 400 to about 800micrometers.

For all of the above embodiments, it will be appreciated that the depthof penetration (DOP) of each of the plurality of microneedles (or theaverage of all of the plurality of microneedles) in a microneedle arraymay not be the full length of the microneedles themselves.

In some embodiments, the microneedle array 107 according to the presentdisclosure can be in the form of a patch, which can include themicroneedle array 107, a skin-contact adhesive, such as those describedabove, and optionally a backing. Whether on a patch or not, themicroneedles 108 can be arranged in any desired pattern or arrangement.For example, the microneedles 108 can be arranged in uniformly spacedrows, which can be aligned or offset. In some embodiments, themicroneedles 108 can be arranged in a polygonal pattern such as atriangle, square, rectangle, pentagon, hexagon, heptagon, octagon, ortrapezoid. In other embodiments, the microneedles 108 can be arranged ina circular or oval pattern.

In some embodiments, the surface area of the substrate 109 covered withmicroneedles 108, can be about 0.1 cm² to about 20 cm². In some of theseembodiments, the surface area of the substrate 109 covered withmicroneedles 108 is about 0.5 cm² to about 5 cm². In some other of theseembodiments, the surface area of the substrate 109 covered withmicroneedles 108 is about 1 cm² to about 3 cm². In still other of theseembodiments, the surface area of the substrate 109 covered withmicroneedles 108 is about 1 cm² to about 2 cm².

In some embodiments, the microneedles 108 of the present disclosure canbe disposed over substantially the entire surface of the array 107(e.g., of the substrate 109). In other embodiments, a portion of thesubstrate 109 may not be provided with microneedles 108 (that is, aportion of the substrate 109 is non-structured). In some of theseembodiments, the non-structured surface has an area of more than about 1percent and less than about 75 percent of the total area of the devicesurface that faces the skin surface 50. In another of these embodiments,the non-structured surface has an area of more than about 0.65 cm² (0.10square inch) to less than about 6.5 cm² (1 square inch).

For hollow microneedles, a hollow channel or bore extends through thesubstrate 109 and microneedles 108. In some embodiments, the bore exitsat a channel opening at or near the tip of the hollow microneedle. Thechannel preferably exits at an opening near the tip of the hollowmicroneedle. Most preferably, the channel or bore continues along acentral axis of the microneedle, but exits similar to a hypodermicneedle on a sloping side-wall of the microneedle to help preventblockage of the channel by tissue upon insertion. In some embodiments,the diameter of the channel bore is about 10 to about 200 micrometers.In other embodiments, the diameter of the channel bore is about 10 toabout 150 micrometers. In still other embodiments, the diameter of thechannel bore is about 30 to about 60 micrometers.

In some embodiments of hollow microneedles, the average cross-sectionalarea of the channel bore is about 75 to about 32,000 micrometers. Inother embodiments of hollow microneedles, the average cross-sectionalarea of the channel bore is about 75 to about 18,000 micrometers. Instill other embodiments of hollow microneedles, the averagecross-sectional area of the channel bore is about 700 to about 3,000micrometers.

In some embodiments of hollow microneedle arrays, the average spacingbetween adjacent microneedles (as measured from microneedle tip tomicroneedle tip) is between about 0.7 mm and about 20 mm. In otherembodiments of hollow microneedle arrays, the average spacing betweenadjacent microneedles is between about 0.7 mm and about 10 mm. In stillother embodiments of hollow microneedle arrays, the average spacingbetween adjacent microneedles is between about 2 mm and about 20 mm. Instill other embodiments of hollow microneedle arrays, the averagespacing between adjacent microneedles is between about 2 mm and about 10mm. In a preferred embodiment of hollow microneedle arrays, the averagespacing between adjacent microneedles is between about 2 mm.

In some embodiments of hollow microneedle arrays, the average spacingbetween adjacent microneedles (as measured from microneedle tip tomicroneedle tip) is greater than about 0.7 mm. In other embodiments ofhollow microneedle arrays, the average spacing between adjacentmicroneedles is greater than about 2 mm.

In some embodiments of hollow microneedle arrays, the average spacingbetween adjacent microneedles is less than about 20 mm. In otherembodiments of hollow microneedle arrays, the average spacing betweenadjacent microneedles is less than about 10 mm.

In some embodiments of solid microneedle arrays, the average spacingbetween adjacent microneedles (as measured from microneedle tip tomicroneedle tip) is between about 200 micrometers and about 2000micrometers. In other embodiments of solid microneedle arrays, theaverage spacing between adjacent microneedles is between about 200micrometers and about 600 micrometers. In still other embodiments ofsolid microneedle arrays, the average spacing between adjacentmicroneedles is between about 200 micrometers and about 300 micrometers.In yet still other embodiments of solid microneedle arrays, the averagespacing between adjacent microneedles is between about 500 micrometersand about 600 micrometers.

In some embodiments of solid microneedle arrays, the average spacingbetween adjacent microneedles (as measured from microneedle tip tomicroneedle tip) is greater than about 200 micrometers. In otherembodiments of solid microneedle arrays, the average spacing betweenadjacent microneedles is greater than about 500 micrometers.

In some embodiments of solid microneedle arrays, the average spacingbetween adjacent microneedles is less than about 2000 micrometers. Inother embodiments of solid microneedle arrays, the average spacingbetween adjacent microneedles is less than about 1000 micrometers. Instill other embodiments of solid microneedle arrays, the average spacingbetween adjacent microneedles is less than about 600 micrometers. In yetstill other embodiments of solid microneedle arrays, the average spacingbetween adjacent microneedles is less than about 300 micrometers.

The microneedle arrays can be manufactured in any suitable way such asby injection molding, compression molding, metal injection molding,stamping, photolithography, or extrusion. In one embodiment, hollowmicroneedle arrays can be made by thermocycled injection molding of apolymer such as medical grade polycarbonate or LCP, followed by laserdrilling to form the channels of the microneedles.

The following embodiments are intended to be illustrative of the presentdisclosure and not limiting.

EMBODIMENTS

1. A microneedle injection apparatus comprising:

-   -   a housing having a base and a cavity that extends through the        base to define an opening in the base, wherein the base of the        housing is configured to be positioned toward a skin surface;    -   a microneedle array holder configured to hold a microneedle        array within the cavity of the housing, the microneedle array        holder configured to be at least partially located in the cavity        of the housing and movable with respect to the opening in the        base of the housing between        -   a retracted position in which the microneedle array is            recessed within the housing such that the microneedle array            does not contact the skin surface when the base of the            housing is positioned on the skin surface and the            microneedle array is coupled to the microneedle array            holder, and        -   an extended position in which at least a portion of the            microneedle array is positioned to contact the skin surface            via the opening when the base of the housing is positioned            on the skin surface and the microneedle array is coupled to            the microneedle array holder; and    -   an actuator movable with respect to the housing and the        microneedle array holder between a first position and a second        position to cause the microneedle array holder to move from the        retracted position to the extended position, wherein at least a        portion of the actuator is located adjacent the base of the        housing and is configured to be moved from the first position to        the second position in response to the apparatus being pressed        toward the skin surface.

2. The apparatus of embodiment 1, wherein the actuator includes a baseconfigured to be positioned toward the skin surface, wherein themicroneedle array holder includes a base configured to be positionedtoward the skin surface, and wherein the distance between the base ofthe actuator and the base of the microneedle array holder decreases whenthe actuator is moved from the first position to the second position.

3. The apparatus of embodiment 1 or 2, wherein the actuator includes abase configured to be positioned toward the skin surface, wherein themicroneedle array holder includes a base configured to be positionedtoward the skin surface, wherein the base of the actuator is positioneda first distance from the base of the microneedle array holder when theactuator is in the first position, wherein the base of the actuator ispositioned a second distance from the base of the microneedle arrayholder when the actuator is in the second position, and wherein thesecond distance is less than the first distance.

4. The apparatus of any of embodiments 1-3, wherein the actuator islocated on a skin-facing side of the apparatus.

5. The apparatus of any of embodiments 1-4, wherein the actuator ismovable between the first position and the second position relative tothe housing and the microneedle array holder when the microneedle arrayholder is in the retracted position.

6. The apparatus of any of embodiments 1-5, wherein the apparatus has afootprint having a first area, and wherein the actuator has a footprinthaving a second area, and wherein the second area is less than half ofthe first area.

7. The apparatus of any of embodiments 1-6, further comprising acartridge located within the housing, the cartridge defining a reservoirconfigured to contain an active agent.

8. The apparatus of embodiment 7, wherein the microneedle array holderis movable independently of the cartridge.

9. The apparatus of embodiment 7 or 8, wherein the cartridge is movablebetween a first position in which the reservoir is not in fluidcommunication with a fluid path and a second position in which thereservoir is in fluid communication with the fluid path.

10. The apparatus of any of embodiments 7-9, wherein movement of theactuator to the second position actuates both (i) movement of themicroneedle array holder to the extended position and (ii) movement ofthe cartridge to the second position.

11. The apparatus of embodiment 9 or 10, further comprising a shuttleconfigured to hold the cartridge in the housing and carry the cartridgebetween the first position and the second position.

12. The apparatus of embodiment 11, wherein the shuttle is configured tohold the actuator in the second position after the actuator has beenmoved to the second position.

13. The apparatus of any of embodiments 1-12, further comprising aninfusion device.

14. The apparatus of any of embodiments 1-13, wherein the microneedlearray includes a first major surface and a plurality of microneedlesthat protrude from the first major surface.

15. The apparatus of any of embodiments 1-14, wherein the plurality ofmicroneedles are hollow, and further comprising a cartridge thatincludes a reservoir configured to contain an active agent, wherein thereservoir and at least some of the plurality of hollow microneedles areconfigured to be in fluid communication when the microneedle array iscoupled to the microneedle array holder and the microneedle array holderis in the extended position, but not when the microneedle array holderis in the retracted position.

16. The apparatus of embodiment 15, wherein the cartridge is carried bya shuttle that is movable between a first position in which thereservoir is not in fluid communication with the plurality ofmicroneedles and a second position in which the reservoir is in fluidcommunication with at least some of the plurality of microneedles.

17. The apparatus of embodiment 16, wherein when the shuttle is in thesecond position, the shuttle is positioned to hold the actuator in thesecond position.

18. The apparatus of embodiment 16 or 17, wherein the shuttle isconfigured to hold the actuator in the second position after theactuator has been moved to the second position.

19. The apparatus of any of embodiments 1-18, wherein the microneedlearray holder is held in the retracted position by a shuttle, and whereinthe shuttle is movable between a first position in which the shuttle ispositioned to hold the microneedle array holder in the retractedposition and a second position in which the microneedle array holder isfree to move to the extended position.

20. The apparatus of embodiment 19, wherein the shuttle is biased towardthe second position, and wherein the shuttle is restrained from movingto the second position by the actuator until the actuator is in thesecond position.

21. The apparatus of embodiment 19 or 20, wherein when the actuator isin its second position, the shuttle is free to move to its secondposition.

22. The apparatus of embodiment 19 or 20, wherein at least a portion ofthe shuttle is configured to hold the actuator in the second positionafter the actuator has been moved to the second position.

23. The apparatus of any of embodiments 1-22, wherein the actuator is atleast partially located in the cavity of the housing.

24. The apparatus of any of embodiments 1-23, wherein the actuator ismovable with respect to the base of the housing, and wherein

-   -   when the actuator is in the first position, an outermost surface        of the actuator extends beyond the base of the housing by a        first distance, and    -   when the actuator is in the second position, the outermost        surface of the actuator        -   does not extend beyond the base of the housing, or        -   extends beyond the base of the housing by a second distance            that is less than the first distance.

25. The apparatus of any of embodiments 1-24, wherein the actuator hasan annular cross-sectional shape and defines an internal bore, andwherein the microneedle array holder is movable in the bore as themicroneedle array holder is moved between the retracted position and theextended position.

26. The apparatus of any of embodiments 1-25, wherein the actuatorincludes a base and a cavity that extends through the base of theactuator to form an opening in the base of the actuator, and wherein themicroneedle array holder is movable in the cavity of the actuatorindependently of the cartridge when the microneedle array holder ismoved between the retracted position and the extended position.

27. The apparatus of embodiment 26, wherein at least a portion of theactuator is movable with respect to the base of the housing into and outof the opening formed in the base of the housing.

28. The apparatus of any of embodiments 1-27, wherein at least a portionof the actuator extends into the cavity of the housing.

29. The apparatus of any of embodiments 1-28, wherein the actuatorincludes a base and an opening formed in the base, and wherein at leasta portion of the microneedle array extends through the opening in theactuator and beyond the base of the actuator when the microneedle arrayholder is in the extended position.

30. The apparatus of embodiment 29, wherein the base of the actuator isconfigured to be coupled to the skin surface.

31. The apparatus of embodiment 29 or 30, wherein the base of theactuator includes a skin-contact adhesive.

32. The apparatus of any of embodiments 1-31, wherein at least a portionof the actuator is located in the cavity of the housing and positionedto at least partially surround the microneedle array, at least when themicroneedle array holder is in the extended position.

33. The apparatus of any of embodiments 1-32, wherein at least a portionof the actuator is located adjacent the opening in the base of thehousing, and wherein at least a portion of the microneedle array extendsbeyond the actuator when the microneedle array holder is in the extendedposition.

34. The apparatus of any of embodiments 1-33, wherein the microneedlearray holder is movable along a first actuation axis between theretracted position and the extended position, and wherein the actuatoris movable between the first position and the second position along asecond actuation axis, and wherein the first actuation axis and thesecond actuation axis are substantially parallel with respect to oneanother.

35. The apparatus of embodiment 34, wherein at least a portion of theactuator extends beyond the base of the housing when the actuator is inthe first position.

36. The apparatus of embodiment 34 or 35, wherein the first actuationaxis and the second actuation axis are substantially aligned.

37. The apparatus of any of embodiments 1-36, wherein the actuator isconfigured to be held in the second position after being moved from thefirst position to the second position.

38. The apparatus of any of embodiments 1-37, further comprising:

-   -   a biasing element positioned to bias the actuator in the first        position, wherein the actuator is movable from the first        position to the second position against the bias of the first        biasing element; and    -   a stored energy device operable to drive the microneedle array        holder from the retracted position to the extended position as a        result of the actuator being moved to the second position.

39. The apparatus of any of embodiments 1-38, further comprising:

-   -   a first biasing element positioned to bias the actuator in the        first position, wherein the actuator is movable from the first        position to the second position against the bias of the first        biasing element; and    -   a second biasing element positioned to bias the microneedle        array holder in the extended position, wherein the microneedle        array holder is held against the bias of the biasing element        when the microneedle array holder is in the retracted position,        and wherein the microneedle array holder is released from being        held against the bias of the biasing element as a result of the        actuator being moved to the second position.

40. The apparatus of any of embodiments 1-39, wherein the microneedlearray holder is biased in the extended position.

41. The apparatus of any of embodiments 1-40, further comprising abiasing element positioned to bias the microneedle array holder in theextended position, wherein the microneedle array holder is held againstthe bias of the biasing element when the microneedle array holder is inthe retracted position, and wherein the microneedle array holder isreleased from being held against the bias of the biasing element as aresult of the actuator being moved to the second position.

42. The apparatus of any of embodiments 1-41, wherein the actuator isbiased in the first position.

43. The apparatus of any of embodiments 1-42, wherein the microneedlearray holder is held in the retracted position, and wherein themicroneedle array holder is released from the retracted position as aresult of the actuator being moved to the second position.

44. The apparatus of any of embodiments 1-43, wherein the actuatorincludes a skin-contact adhesive, and wherein the housing is configuredto be coupled to the skin surface at least via the skin-contact adhesiveon the actuator.

45. The apparatus of any of embodiments 1-44, wherein the actuatorincludes a skin-contact adhesive.

46. The apparatus of any of embodiments 1-45, wherein, when the actuatoris in the first position, at least a portion of the actuator protrudesfrom the opening in the base of the housing and defines a baseconfigured to be coupled to the skin surface.

47. The apparatus of embodiment 46, wherein the base of the actuatorincludes a skin-contact adhesive.

48. The apparatus of any of embodiments 1-47, wherein the microneedlearray holder includes a base configured to be positioned toward a skinsurface, and further comprising the microneedle array, wherein themicroneedle array is coupled to the base of the microneedle array holderand is movable with the microneedle array holder between the retractedand the extended position.

49. The apparatus of any of embodiments 1-48, wherein at least a portionof the actuator is located on a skin-facing portion of the apparatus andis configured to be moved from the first position to the second positionin response to the apparatus being pressed toward a skin surface bypressing on a non-skin-facing portion of the apparatus.

50. The apparatus of embodiment 49, wherein the non-skin-facing portionof the apparatus is located in an off-axis position with respect to anactuation axis of the actuator.

51. The apparatus of any of embodiments 1-50, wherein at least a portionof the actuator is located on a lower portion of the housing, andwherein the actuator is configured to be moved from the first positionto the second position in response to the apparatus being pressed towarda skin surface by pressing on an upper portion of the housing.

52. The apparatus of embodiment 51, wherein the upper portion of thehousing is located in an off-axis position with respect to an actuationaxis of the actuator.

53. The apparatus of any of embodiments 1-52, wherein the actuator isconfigured to be moved from the first position to the second positionwhen a non-skin-facing portion of the housing is pressed.

54. The apparatus of embodiment 53, wherein the non-skin-facing portionof the housing is not located directly opposite the portion of theactuator located adjacent the base of the housing.

55. The apparatus of any of embodiments 53 or 54, wherein thenon-skin-facing portion of the housing is located in an off-axisposition with respect to an actuation axis of the actuator.

56. The apparatus of any of embodiments 1-55, wherein at least a portionof the housing is configured to be pressed using any portion of a hand.

The embodiments described above and illustrated in the figures arepresented by way of example only and are not intended as a limitationupon the concepts and principles of the present disclosure. As such, itwill be appreciated by one having ordinary skill in the art that variouschanges in the elements and their configuration and arrangement arepossible without departing from the spirit and scope of the presentdisclosure.

All references and publications cited herein are expressly incorporatedherein by reference in their entirety into this disclosure.

Various features and aspects of the present disclosure are set forth inthe following claims.

What is claimed is:
 1. A microneedle injection apparatus comprising: ahousing having a base and a cavity that extends through the base todefine an opening in the base, wherein the base of the housing isconfigured to be positioned toward a skin surface; a microneedle arrayholder configured to hold a microneedle array within the cavity of thehousing, the microneedle array holder configured to be at leastpartially located in the cavity of the housing and movable with respectto the opening in the base of the housing between a retracted positionin which the microneedle array is recessed within the housing such thatthe microneedle array does not contact the skin surface when the base ofthe housing is positioned on the skin surface and the microneedle arrayis coupled to the microneedle array holder, and an extended position inwhich at least a portion of the microneedle array is positioned tocontact the skin surface via the opening when the base of the housing ispositioned on the skin surface and the microneedle array is coupled tothe microneedle array holder; and an actuator movable with respect tothe housing and the microneedle array holder between a first positionand a second position to cause the microneedle array holder to move fromthe retracted position to the extended position, wherein at least aportion of the actuator is located adjacent the base of the housing andis configured to be moved from the first position to the second positionin response to the apparatus being pressed toward the skin surface,wherein the actuator is movable with respect to the base of the housing,wherein when the actuator is in the first position, an outermost surfaceof the actuator extends beyond the base of the housing by a firstdistance, and when the actuator is in the second position, the outermostsurface of the actuator does not extend beyond the base of the housing,or extends beyond the base of the housing by a second distance that isless than the first distance, and wherein the actuator is an invertedactuator having at least a portion of the actuator located on the sameside of the housing as the base that is configured to be positionedtowards a skin surface.
 2. The apparatus of claim 1, wherein theactuator includes a base configured to be positioned toward the skinsurface, wherein the microneedle array holder includes a base configuredto be positioned toward the skin surface, wherein the base of theactuator is positioned a third distance from the base of the microneedlearray holder when the actuator is in the first position, wherein thebase of the actuator is positioned a fourth distance from the base ofthe microneedle array holder when the actuator is in the secondposition, and wherein the second distance is less than the firstdistance.
 3. The apparatus of claim 1, wherein the actuator is locatedon a skin-facing side of the apparatus.
 4. The apparatus of claim 1,wherein the apparatus has a footprint having a first area, and whereinthe actuator has a footprint having a second area, and wherein thesecond area is less than half of the first area.
 5. The apparatus ofclaim 1, further comprising a cartridge located within the housing, thecartridge defining a reservoir configured to contain an active agent,wherein the microneedle array holder is movable independently of thecartridge, and wherein movement of the actuator to the second positionactuates both (i) movement of the microneedle array holder to theextended position and (ii) movement of the cartridge to the secondposition.
 6. The apparatus of claim 1, wherein the plurality ofmicroneedles are hollow, and further comprising a cartridge thatincludes a reservoir configured to contain an active agent, wherein thereservoir and at least some of the plurality of hollow microneedles areconfigured to be in fluid communication when the microneedle array iscoupled to the microneedle array holder and the microneedle array holderis in the extended position, but not when the microneedle array holderis in the retracted position.
 7. The apparatus of claim 1, wherein themicroneedle array holder is held in the retracted position by a shuttle,and wherein the shuttle is movable between a first shuttle position inwhich the shuttle is positioned to hold the microneedle array holder inthe retracted position and a second shuttle position in which themicroneedle array holder is free to move to the extended position. 8.The apparatus of claim 1, wherein the actuator includes a base and anopening formed in the base, and wherein at least a portion of themicroneedle array extends through the opening in the actuator and beyondthe base of the actuator when the microneedle array holder is in theextended position.
 9. The apparatus of claim 8, wherein the base of theactuator is configured to be coupled to the skin surface.
 10. Theapparatus of claim 1, wherein at least a portion of the actuator islocated in the cavity of the housing and positioned to at leastpartially surround the microneedle array, at least when the microneedlearray holder is in the extended position.
 11. The apparatus of claim 1,wherein the actuator is configured to be held in the second positionafter being moved from the first position to the second position. 12.The apparatus of claim 1, further comprising: a biasing elementpositioned to bias the actuator in the first position, wherein theactuator is movable from the first position to the second positionagainst the bias of the first biasing element; and a stored energydevice operable to drive the microneedle array holder from the retractedposition to the extended position as a result of the actuator beingmoved to the second position.
 13. The apparatus of claim 1, wherein theactuator includes a skin-contact adhesive, and wherein the housing isconfigured to be coupled to the skin surface at least via theskin-contact adhesive on the actuator.
 14. The apparatus of claim 1,wherein at least a portion of the actuator is located on a lower portionof the housing, wherein the actuator is configured to be moved from thefirst position to the second position in response to the apparatus beingpressed toward a skin surface by pressing on an upper portion of thehousing, and wherein the upper portion of the housing is located in anoff-axis position with respect to an actuation axis of the actuator.